Phytomedicine 114 (2023) 154771

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Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Review

Cannabidiol goes nuclear: The role of PPARγ

Sara Khosropoor a, Mohaddeseh Sadat Alavi b, Leila Etemad c, Ali Roohbakhsh d, *
a
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
b
Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
c
International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
d
Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Cannabidiol (CBD) is one of the main phytocannabinoids found in Cannabis sativa. In contrast to Δ9-
Cannabidiol tetrahydrocannabinol, it has a low affinity for cannabinoid receptors CB1 and CB2, thereby it does not induce
Phytocannabinoids significant psychoactive effects. However, CBD may interact with other receptors, including peroxisome
Cannabis sativa, PPARγ
proliferator-activated receptor gamma (PPARγ). CBD is a PPARγ agonist and changes its expression. There is
considerable evidence that CBD’s effects are mediated by its interaction with PPARγ. So, we reviewed studies
related to the interaction of CBD and PPARγ.
Methods: In this comprehensive literature review, the term ‘cannabidiol’ was used in combination with the
following keywords including ‘PPARγ’, ‘Alzheimer’s disease’, ‘Parkinson’s disease’, ‘seizure’, ‘multiple sclerosis’,
‘immune system’, ‘cardiovascular system’, ‘cancer’, and ‘adipogenesis’. PubMed, Web of Science, and Google
Scholar were searched until December 20, 2022. A total of 78 articles were used for the reviewing process.
Results: CBD, via activation of PPARγ, promotes significant pharmacological effects. The present review shows
that the effects of CBD on Alzheimer’s disease and memory, Parkinson’s disease and movement disorders,
multiple sclerosis, anxiety and depression, cardiovascular system, immune system, cancer, and adipogenesis are
mediated, at least in part, via PPARγ.
Conclusion: CBD not only activates PPARγ but also affects its expression in the body. It was suggested that the late
effects of CBD are mediated via PPARγ activation. We suggested that CBD’s chemical structure is a good
backbone for developing new dual agonists. Combining it with other chemicals enhances their biological
effectiveness while reducing their dosage. The present study indicated that PPARγ is a key target for CBD, and its
activation by CBD should be considered in all future studies.

Introduction (Melas et al., 2021; Premoli et al., 2019; Rock et al., 2012; Rudroff and
Sosnoff, 2018; Stanley et al., 2013; Verrico et al., 2020). This wide range
Cannabis sativa is a medicinal plant with many active compounds, of applications suggests diverse cellular targets for CBD. Indeed, CBD
including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has a rich pharmacology with numerous biological targets. After FDA
(Martínez et al., 2020). Δ9-THC is a phytocannabinoid with psychoac­ approval of Epidiolex® for the treatment of Dravet and Lennox-Gastaut
tive properties, while CBD is devoid of such properties. However, CBD syndromes (Devinsky et al., 2017; Thiele et al., 2018) and the recent
has been used in the treatment of a wide range of diseases and disorders, legalization of commercial hemp, CBD has gained much more attention.
such as psychosis, depression, epilepsy, anxiety, addiction, multiple Its applications in the treatment of anxiety (Berger et al., 2022),
sclerosis, cardiovascular and inflammatory diseases, rheumatoid post-traumatic stress disorder (PTSD) (Das et al., 2013), psychosis
arthritis, emesis, Parkinson’s, Alzheimer’s, and Huntington’s diseases (Devinsky et al., 2014), cognitive dysfunction (McCartney et al., 2022),

Abbreviations: Δ9-thc, Δ9-tetrahydrocannabinol; aims, Abnormal involuntary movements; ap-1, Activator protein 1; aβ, Amyloid beta; app, Amyloid precursor
protein; ace-2, Angiotensin-converting enzyme 2; bbb, Blood-brain barrier; bm-mscs, Bone marrow-derived mesenchymal stem cells; bccao, Bilateral common carotid
artery occlusion; cat, Catalase; cbd, Cannabidiol; cb1, Cannabinoid receptor 1; cb2, Cannabinoid receptor 2; cns, Central nervous system; cipn, Chemotherapy-
induced peripheral neuropathy; cxcl1, C-x-c motif chemokine ligand 1; cox-2, Cyclooxygenase-2; egc, Enteric glial cells; egf, Epidermal growth factor; egfr, Epidermal
growth factor receptor.
* Corresponding author at: Ferdowsi University complex, Vakil abad Boulevard, P.O. Box: 917751365, Mashhad, Iran. Tel: +9851-31801180.
E-mail address: [email protected] (A. Roohbakhsh).

https://doi.org/10.1016/j.phymed.2023.154771
Received 8 October 2022; Received in revised form 6 February 2023; Accepted 14 March 2023
Available online 15 March 2023
0944-7113/© 2023 Elsevier GmbH. All rights reserved.
S. Khosropoor et al. Phytomedicine 114 (2023) 154771

and dementia (Kłosińska and Leszko, 2022) have been reported with subtypes: PPARα, PPARβ/δ, and PPARγ. They participate in several
positive results. cellular functions, including respiration, metabolism, differentiation,
It was reported that consumption of a marijuana cigarette (1 g) el­ and development (Mirza et al., 2019) and serve as the main regulators of
evates CBD concentration up to 0.056 μg/ml in the serum (Pacifici et al., energy homeostasis and glucose and lipid metabolism. PPARγ has two
2020). Cannabinoids and endocannabinoids (e.g., anandamide and distinct isoforms designated as PPARγ1 and PPARγ2. PPARγ1 is
2-arachidonoylglycerol) act primarily on two cannabinoid receptors, the expressed in almost all tissues, while PPARγ2 is expressed almost
CB1 and CB2 receptors (Hajizadeh Moghaddam et al., 2013). Although exclusively in the adipose tissue (Ahmadian et al., 2013). Due to its
CBD has little or no binding affinity for these targets (Navarro et al., different structure, PPARγ2 has 5- to 10-fold ligand-independent acti­
2018). So, the discovery of biological targets other than CB1 and CB2 vation compared to PPARγ1, with an important role in effective adipo­
has been pursued in many recent studies. CBD binds various receptors, genesis (Wu et al., 2020). Several endogenous ligands for PPARγ have
including the orphan G protein-coupled receptors; GPR3, GPR6, GPR12, been identified, mainly belonging to unsaturated fatty acids, including
and GPR55 (Laun et al., 2019; Whyte et al., 2009), α2 adrenergic, petroselinic acid, arachidonic acid, linolenic acid, and linoleic acid
(Cascio et al., 2010), dopamine D2 (Seeman, 2016), γ-aminobutyric acid (Kliewer et al., 1997). PPARγ ligands promote PPARγ heterodimer with
type A (GABAA) (Bakas et al., 2017), adenosine A2A (Carrier et al., another nuclear receptor, the retinoid X receptor (RXR). The functions of
2006), glycine (Ahrens et al., 2009), serotonin 5-HT1A (Galaj et al., PPARγ get altered by the binding ligand shape and the presence of
2020), and μ- and δ-opioid receptors (Kathmann et al., 2006). It also coactivator or corepressor proteins. When no ligand is present, PPARγ
binds T-type (Ross et al., 2008) and l-type voltage-regulated Ca2+ and RXR heterodimer binds with the corepressor and suppress gene
channels (Isaev et al., 2022), and peroxisome proliferator-activated re­ transcription (Privalsky, 2004). In contrast, specific ligands lead to
ceptor gamma (PPARγ) (Mlost et al., 2021), and has significant modu­ recruitment of the coactivator and release the corepressor that induces
latory effects on various transient potential (TRP) channels (Etemad activation of the basal transcriptional machinery. So, PPARγ changes the
et al., 2022). expression of various genes implicated in glucose homeostasis, insulin
PPARγ belongs to a family of nuclear receptors having three release, lipid metabolism, inflammation, and immunity (Fig. 1)

Fig. 1. A schematic illustration of the physiological effects of PPARγ in the body. Green arrows show beneficial effects and red arrows show adverse effects. Adi­
pogenesis in white adipose tissue is presumed to be an adverse effect while in brown adipose it is presumed to be a good effect.

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(Ahmadian et al., 2013). PPARγ activates nuclear erythroid 2-related

factor (Nrf2), which provokes the expression of major antioxidant pro­
teins such as glutathione S-transferase (GST), catalase (CAT),
heme-oxygenase-1 (HO-1), and manganese-dependent superoxide dis­
mutase (Mn-SOD) (Hussein et al., 2019; Nguyen et al., 2009). PPARγ
also inhibits the transcriptional activities of several transcription factors
including activator protein 1 (AP-1), signal transducer and activator of
transcription (STAT), nuclear factor-kappa B (NF-kB), and cell signaling
proteins, including mitogen-activated protein (MAP) kinases (Carvalho
et al., 2021). NF-kB has a crucial role in the activation of various
pro-inflammatory gene expressions such as tumor necrosis factor-α
(TNF-α), cyclooxygenase-2 (COX-2), interleukin-1 (IL-1), IL-6, and IL-12
(Liu et al., 2017). PPARγ agonists (thiazolidinediones) such as piogli­
tazone and rosiglitazone are used for treating type II diabetes. However,
they have been used in the treatment of various diseases such as cancer
(Yee et al., 2007), Alzheimer’s disease (Sato et al., 2011), depression
(Kemp et al., 2014), and rheumatoid arthritis (Ormseth et al., 2013).
This wide range of clinical applications is in accordance with multiple
PPARγ cellular targets that were mentioned previously.
However, thiazolidinediones may exacerbate congestive heart fail­
ure in some patients (Chaggar et al., 2009). These drugs may increase
Fig. 2. The diagram of the search strategy.
the risk of bladder cancer and bone fractures (Murphy and Rodgers,
Flow chart of literature search showing the included and excluded (duplicated,
2007; Tseng, 2014). The underlying mechanism is not well established, non-relevant, and non-English language) studies. A total of 78 articles were
but it may result from activation of PPARγ. PPARγ activation alters included in the current review.
tumor growth and progression in non-adipose cells. Its activation in
bone creates an imbalance in bone remodeling, including changes in CBD and PPARγ interaction in the central nervous system
bone marrow structure and function. Thiazolidinediones may also
impair bone function by reducing estrogen synthesis (Murphy and PPARγ, under physiological conditions, is expressed in the central
Rodgers, 2007). nervous system (CNS) at low levels (Bookout et al., 2006). However, in
CBD is an agonist of the PPARγ (Granja et al., 2012) and has little or some pathological conditions, including Alzheimer’s disease (AD), its
no affinity for PPARα (D’Aniello et al., 2019). Likewise, some cannabi­ expression is elevated (de la Monte and Wands, 2006). Astrocytes have
noids, such as THC (O’Sullivan et al., 2005) and the endocannabinoids the highest level of PPARγ expression in the CNS (Fernandez et al.,
2-arachidonoylglycerol and anandamide, have affinities for PPARγ 2017). PPARγ activation promotes neurite outgrowth in mature neurons
(Gasperi et al., 2007). CBD not only binds PPARγ but also changes its (Miglio et al., 2009). These findings imply the pivotal role of PPARγ in
expression (Hegde et al., 2015; O’Sullivan et al., 2009). Considering the regulating the pathophysiological characteristics of AD and other
safety and tolerability of CBD in clinical practice (McCartney et al., neurological disorders. Accordingly, PPARγ has been reported as a
2022; O’Brien et al., 2022) and its growing consumption (Rapin et al., therapeutic target for treating major neurodegenerative diseases
2021), we have to expand our knowledge regarding the biological tar­ (Agarwal et al., 2017).
gets of CBD. Considerable evidence shows that PPARγ is a key target for
CBD. Indeed, many effects of CBD can be prevented by PPARγ antago­
nists. Based on these findings, for the first time, we aimed to review the Alzheimer’s disease and memory
studies related to the interaction of CBD and PPARγ and discuss the
importance of such interaction in pre-clinical and clinical studies. AD is a neurodegenerative age-dependent disease characterized by
cognitive function and memory decline. The main pathological findings
Methods include tau protein hyperphosphorylation (neurofibrillary tangles) and
amyloid beta (Aβ) protein aggregation forming plaque deposits. Chronic
Search strategy inflammation and oxidative stress are associated with the development
of AD (Bisht et al., 2018). Neuroinflammation during AD up-regulates
In this comprehensive literature review, the term ‘cannabidiol’ was PPARγ (de la Monte and Wands, 2006), and its activation promotes
used in combination with the following keywords including ‘PPARγ’, anti-inflammatory responses during AD (Vallée et al., 2017). PPARγ
‘Alzheimer’s disease’, ‘Parkinson’s disease’, ‘seizure’, ‘multiple scle­ agonists have beneficial effects on AD (Quan et al., 2019). Activation of
rosis’, ‘immune system’, ‘cardiovascular system’, ‘cancer’, ‘adipo­ wingless-related integration site (Wnt)/β-catenin signaling inhibits
genesis’. PubMed, Web of Science, Scopus, and Google Scholar were glycogen synthase kinase-3β (GSK-3β) activity that is associated with tau
used as electronic databases. No time limitation (up to December 20, hyperphosphorylation (Jia et al., 2019). CBD has been reported with
2022) was considered in this review. The search strategy used for the inhibitory action on GSK-3β activity with reduced tau hyper­
present article follows the PRISMA 2009 checklist and is listed in Fig. 2. phosphorylation function (Esposito et al., 2006). Likewise, PPARγ
stimulation decreases GSK-3β activity (Ban et al., 2010). An aberrant
cleavage of amyloid precursor protein (APP) increases Aβ formation
Study selection triggering the accumulation of Aβ fibrils in senile plaques. Accordingly,
the effect of CBD on AD was assessed using an in vitro model. The re­
Non-English publications and dissertations were ineligible for in­ searchers showed that exposure to CBD provoked ubiquitination of APP
clusion. In the primary search, 231 studies were included. Then, dupli­ protein which decreased APP full-length protein level in SHSY5YAPP+
cate researches were removed. Screening of the remaining articles was neurons. The final result was lower Aβ production and neuronal
performed by reading the titles, abstracts, or full texts according to the apoptosis that was prevented by a PPARγ antagonist (Scuderi et al.,
eligibility criteria. A total of 78 articles were included in the reviewing 2014). In line with the previous study, CBD reduced neuroinflammation
process. by preventing NO, TNF-α, and IL-1β production in the rat astrocytes. It

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also suppressed Aβ-induced up-regulation of inducible nitric oxide response elicited by haloperidol. CBD also enhanced mRNA expression
synthase (iNOS), astroglial signaling neurotrophin (S100B), and glial of peroxisome proliferator-activated receptor gamma coactivator
fibrillary acidic protein (GFAP) via NF-κB (both p50 and p65) inhibition. 1-alpha (PGC-1α), a PPARγ coactivator, similar to the effect of rosigli­
These effects were mediated via PPARγ activation. The effect of CBD on tazone on PGC-1α (Jin et al., 2013). The study also showed that CBD
neuronal survival and Aβ-induced reactive gliosis in rat hippocampus exposure reduced lipopolysaccharide (LPS)-induced microglia activa­
was also investigated. CBD rescued CA1 pyramidal neuron integrity, tion, NF-κB translocation, and oxidative stress that were prevented by
reduced gliosis, and restored neurogenesis in the dentate gyrus. These GW9662 (Sonego et al., 2018). Similar to the previous study, CBD not
effects vanished following pre-treatment with a PPARγ antagonist only decreased haloperidol-induced orofacial dyskinesia but also
(Esposito et al., 2011). Using hippocampal slices, the effect of CBD on increased memory function in the novel object recognition test in mice.
the neurotoxic effects of Aβ was assessed in another study. The results This finding implies that cognitive deficits induced by haloperidol were
showed that acute exposure to CBD ameliorated Aβ-induced deficits in reversed by CBD. The researchers reported that the striatal and hippo­
long-term potentiation (LTP) independent of serotonin 5-HT1A, aden­ campal levels of IL-1β and TNF-α had a positive correlation with vacuos
osine A2A, or CB1 receptors. Treatment with a PPARγ antagonist chewing movements confirming the inflammatory basis of TD. The ef­
reduced LTP levels in Aβ- and CBD-treated hippocampal slices implying fects of CBD on orofacial dyskinesia were reversed following the
a role for PPARγ in the modulation of LTP as a core neuronal process administration of GW9662 (Sonego et al., 2021). Of note, the beneficial
underlying long-term memory (Hughes and Herron, 2019). The extinc­ effect of pioglitazone, an agonist of PPARγ receptors, against
tion of memory is a useful process for ameliorating intrusive memories, haloperidol-induced orofacial dyskinesia has been reported elsewhere
especially in patients with PTSD. It was reported that CBD ameliorated (Grover et al., 2013). In summary, these studies show that CBD could
fear memories by facilitating extinction. Administration of CBD right modify movement abnormalities of dopaminergic and
after or one hour following fear conditioning reduced memory consoli­ anti-dopaminergic drugs used to treat Parkinson’s disease and psychosis.
dation. The effect of CBD given right after fear conditioning was pre­
vented by CB1 or CB2 receptor antagonists but not via PPARγ receptor Multiple sclerosis
blockade. However, CBD effects given one hour after fear conditioning
were suppressed exclusively by the PPARγ receptor antagonist. Ac­ Multiple sclerosis (MS) is a neurodegenerative disease with
cording to these findings, the researchers proposed the time-dependent numerous clinical features. The main pathological finding is the demy­
involvement of anandamide, CB1, CB2, and PPARγ receptors in the elination of the neurons in the CNS. Previous studies have offered a
disruptive action of CBD on memory consolidation in the dorsal hip­ protective role for PPARγ activators against MS (Liu et al., 2020; Vallée
pocampus (Raymundi et al., 2020). The mentioned studies show that et al., 2018). The effects of CBD and Δ9-THC were investigated in a viral
PPARγ partly mediates the beneficial effects of CBD on AD. model of MS. The results indicated that CBD abolished motor deficits of
SJL/J mice better than Δ9-THC. Treatment with a PPARγ antagonist,
Parkinson’s disease and movement disorders T0070907, blocked the effects of CBD, while the beneficial effects of
Δ9-THC were attenuated only by CB1 and CB2 antagonists (Feliú et al.,
Parkinson’s disease is another neurodegenerative disease with a 2015). The potential of CBD in treating MS was also evaluated in the
complicated pathology (Chow and Chin, 2020). One of the main experimental autoimmune encephalomyelitis (EAE) as a valid preclini­
biochemical findings is lower dopamine in certain brain areas, which is cal model of MS. The results indicated that CBD treatment improved
attributed to dopaminergic neuron degeneration. l-DOPA, which is MS-like signs in EAE mice (Giacoppo et al., 2017). CBD reduced inter­
converted to dopamine in the body, is a commonly prescribed medica­ feron-γ (IFN-γ) and IL-17 and promoted neuronal survival along with an
tion for Parkinson’s disease. However, its long-term use promotes mul­ up-regulation of PPARγ. The researchers presumed that the
tiple motor and non-motor complications, including l-DOPA-induced anti-inflammatory property of CBD was mediated via PPARγ
dyskinesia. It is recognized by dystonic and choreiform movements up-regulation. Taken together, PPARγ activation has positive effects on
(Huot et al., 2013). Administration of l-DOPA to striatal lesioned mice MS, and part of the protective effects of CBD on MS is elicited by PPARγ
for 21 days induced severe locomotor, limb, axial, and orofacial activation.
abnormal involuntary movements (AIMs) (Dos-Santos-Pereira et al.,
2016). The study showed that CBD did not modify AIMs alone, but when Anxiety and depression
combined with capsazepine, as a TRPV1 antagonist, it reduced AIMs.
Administration of a CB1 antagonist reduced the antidyskinetic effect of Global cerebral ischemia is exhibited following a sudden reduction of
CBD plus capsazepine, mainly limb and orofacial AIMs, while adminis­ cerebral blood flow and subsequent shortage of oxygen and nutrients in
tration of a PPARγ antagonist diminished axial AIMs. The beneficial the brain that may cause neuronal loss and neurodegeneration. It may
effects of CBD plus capsazepine on l-DOPA-induced dyskinesia were lead to long-lasting disabilities, including motor, cognitive, and
concomitant with elevated levels of phosphorylated extracellular emotional impairments (Kim, 2016). Mori et al. induced a mouse model
signal-regulated protein kinases 1 and 2 (p-ERK1/2) and of bilateral common carotid artery occlusion (BCCAO) and adminis­
phospho-acetylated histone H3 and suppression of NF-κB and COX-2 trated CBD before and after reperfusion (Mori et al., 2021). The animals
production in the lesioned striatum. However, the researchers did not were evaluated using various behavioral tests. CBD suppressed
report which effect(s) were mediated via PPARγ (Dos-Santos-Pereira anxiety-like behaviors, memory impairment, and despair-like behaviors
et al., 2016). Tardive dyskinesia (TD) is a hyperkinetic movement dis­ evoked by BCCAO. The anxiolytic-like and antidepressant-like effects of
order that results from repeated use of anti-dopaminergic drugs such as CBD were prevented by CB1, CB2, 5-HT1A, and PPARγ receptor an­
antipsychotics. It is described by involuntary and repetitive movements, tagonists (Mori et al., 2021). Although CBD did not modify locomotor
mainly in the orofacial region (Hauser et al., 2022). The pathophysi­ activity in the elevated zero maze, pre-treatment with 5-HT1A and
ology of TD is not well understood, but inflammation is a determinant PPARγ receptor antagonists decreased general locomotor activity, sug­
parameter (Lim et al., 2021). The putative potential of CBD in the pre­ gesting interference of 5-HT1A and PPAR-γ receptors (Mori et al., 2021).
vention of TD was investigated by Sonego et al. (Sonego et al., 2018).
They showed that chronic administration of haloperidol, a typical Seizure
antipsychotic drug, provoked orofacial dyskinesia, oxidative stress, and
inflammatory changes in mice that were reversed by CBD pre-treatment. The anti-epileptic effect of CBD has been extensively studied in
Administration of GW9662, a PPARγ antagonist, prevented vacuos preclinical and clinical studies (Klein et al., 2017; O’Brien et al., 2022).
chewing movements induced by haloperidol without changing the main It has been approved by the FDA for the treatment of Dravet and

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Lennox-Gastaut syndromes as drug-resistant epilepsies (Devinsky et al., system.

2017; Thiele et al., 2018). A recent study showed that administration of
CBD for three days in rats with temporal lobe epilepsy decreased total CBD and PPARγ interaction in the immune system
seizure duration and occurrence and 50% of rats were seizure free
(Costa et al., 2022). The study showed that CBD at the dose of 12 mg/kg PPARγ expression may alter under inflammatory conditions (Wahli
enhanced PPARγ levels in the subfield and subiculum of hippocampal and Michalik, 2012). It inhibits gene expression of various
CA1. CBD, at the highest dose (120 mg/kg), also increased the PPARγ pro-inflammatory mediators, including NO, IL-1β, IL-6, TNF-α, iNOS,
level in the hippocampal CA3 subfield, amygdala, and perirhinal cortex. and COX-2 via NF-κB inhibition (Liu et al., 2017). In addition, PPARγ
It was concluded that CBD, at least in part, mediates the anti-seizure promotes macrophage differentiation to the anti-inflammatory M2
effect of CBD. It is worth mentioning that the anti-seizure properties phenotype and suppresses the pro-inflammatory M1 phenotype (Bouh­
of PPARγ ligands have been reported (Adabi Mohazab et al., 2012; lel et al., 2007). PPARγ receptor has been associated with cell apoptosis,
Hussein et al., 2019). See Table 1 for a summary of the PPARγ-mediated proliferation, and reduction of reactive oxygen species (ROS) damage
effects of CBD. (Giampietro et al., 2019). In accordance, it was reported that CBD’s
protective action on ischemic brain injury was mediated through sup­
CBD and PPARγ interaction in the cardiovascular system pression of NF-кB, TNF-α, and TNF receptor 1 (TNFR1) (Khaksar and
Bigdeli, 2017). CBD also promoted inhibitory activity on inflammatory
CBD has been reported as a vasorelaxant agent that reduces mean mediators’ release in astrocytes. In this study, Aβ-challenged astrocytes
arterial blood pressure without affecting the heart rate (Walsh et al., were exposed to CBD in the presence or absence of a PPARγ antagonist.
2010). The vasorelaxant effect of CBD on human mesenteric arteries has Treatment with Aβ for 24 h enhanced NO, IL-1β, TNF-α, S100B, and
been reported (Stanley et al., 2015). The respective molecular basis was GFAP levels, which were suppressed by CBD treatment,
investigated in the isolated rat small mesenteric arteries (sMAs) and concentration-dependently. In the presence of a PPARγ antagonist, CBD
human pulmonary arteries (hPAs) (Baranowska-Kuczko et al., 2020). effects were abolished. In addition, CBD, via down-regulation of p50 and
The results showed that CBD promoted a full concentration- and p65, inhibited NF-κB-mediated up-regulation of GFAP, iNOS, and S100B
time-dependent vasorelaxation effect in hPAs and rat sMAs. In hPAs, the protein (Esposito et al., 2011). The researchers also assessed the effect of
vasorelaxant effect was reduced following COX, TRPV1, and PPARγ CBD on reactive gliosis and neuronal survival in the rat hippocampi.
inhibition, as well as in overweight, hypercholesteremic, and hyper­ Injection of Aβ into the CA1 region of the hippocampus caused marked
tensive patients. CB1 or CB2 receptor antagonists did not modify the astrocytic activation along with severe neuronal loss. Administration of
vasorelaxant effect of CBD (Baranowska-Kuczko et al., 2020). In a study CBD for 15 days promoted a significant neuroprotective effect in the
by O’Sullivan et al., it was reported that CBD induced time-dependent CA1 area and down-regulated the gliosis entity which vanished
(over two hours) vasorelaxation of the preconstricted aorta. Its vaso­ following administration of a PPARγ antagonist (Esposito et al., 2011).
relaxant effect was inhibited by PPARγ antagonism and superoxide Using an in vitro model, CBD promoted a significant anti-inflammatory
dismutase inhibition and was not blocked following iNOS, TRPV1, CB1, response in mouse astrocytes activated by LPS that was reflected by
or CB2 receptor inhibition. The researchers showed that CBD-induced the reduced level of IL-6. This effect of CBD was attributed to the inhi­
vasorelaxation in the isolated rat aorta was mainly associated with bition of LPS-triggered phosphorylation of NF-κB and STAT3 pathways
calcium channel inhibition. Using the luciferase reporter assay, the re­ in astrocytes that was not mediated by PPARγ (Wu et al., 2021). Simi­
searchers indicated that CBD enhanced the transcriptional activity of larly, the inhibitory effect of CBD on TNF-α and IL-1β release in mouse
PPARγ. They also showed that CBD bound to PPARγ and provoked the microglia cells was CB2 receptor- but not PPARγ-dependent (Dos-­
differentiation of 3T3-L1 fibroblasts into adipocytes (O’Sullivan et al., Santos-Pereira et al., 2020).
2009). The time-dependent vasorelaxant effect of CBD has also been Inflammation is a major finding of osteoarthritis associated with
reported in the human mesenteric artery (Stanley et al., 2015). This cartilage loss and pain. Administration of CBD to mice with experi­
effect of CBD was blunted in males and patients with hypercholester­ mental osteoarthritis showed significant beneficial effects on weight
olemia or diabetes. However, in contrast to the previous study, the bearing and pain. Administration of a PPARγ antagonist prevented
vasorelaxant effect was mediated by CB1 and TRPV1 receptors and was weight bearing but did not affect heat or mechanical hypersensitivity.
insensitive to PPARγ, CB2, or COX inhibition (Stanley et al., 2015). The study showed that CBD inhibited PPARγ gene expression in the
Wheal et al. also showed that the vasorelaxant effect of CBD in the lumbar spinal cord (Mlost et al., 2021). Myeloid-derived suppressor cells
femoral artery was mediated by CB2 receptors, but not via CB1 or PPARγ (MDSC) are differentiated, immature myeloid cells that serve as a
activation (Wheal et al., 2014). CBD also evoked a relaxant effect on rat immunosuppressive phenotype. They have a notable function in cancer
ventricular myocytes that was independent of PPARγ (Ali et al., 2015). and inflammation as they block the cytotoxic functions of natural killer
The efficacy of CBD on vascular permeability has been investigated as (NK) and NK T cells, and immune responses elicited by CD4+ and CD8+
well. Hind et al., using human brain microvascular endothelial cells T cells (Dolcetti et al., 2008). It is presumed that precursor myeloid cells
(HBMECs), assessed the effect of CBD against oxygen-glucose depriva­ differentiate into mature macrophages, granulocytes, or dendritic cells
tion-enhanced permeability of the blood-brain barrier (BBB) (Hind et al., as they reside in peripheral organs. However, some mediators released
2016). The results indicated that CBD reduced BBB permeability and during infections, cancer, trauma, or autoimmunity promote the pro­
vascular cell adhesion molecule 1 (VCAM-1) and enhanced vascular liferation of immature myeloid cells while preventing their final differ­
endothelial growth factor (VEGF). These effects were prevented in the entiation phenomenon that causes the accumulation of
presence of a PPARγ antagonist. Noteworthy, similar to CBD, it was immunosuppressive MDSC phenotype (Bronte, 2009). It was demon­
demonstrated that troglitazone, as a PPARγ agonist, increased VEGF strated that administration of CBD to naive mice triggered substantial
levels in mouse preadipocytes, which were prevented by GW9662 induction of CD11b+Gr-1+ MDSC in the peritoneum. CBD administra­
(Kotake and Hirasawa, 2013). The beneficial effect of CBD on experi­ tion induced granulocyte-colony stimulating factor (G-CSF), C-X-C motif
mental pulmonary artery hypertension (PAH) was reported by Lu et al. chemokine ligand 1 (CXCL1), and macrophage colony-stimulating factor
(Lu et al., 2021). During this disease, the proliferation of pulmonary (M-CSF), but not granulocyte-macrophage colony-stimulating factor
artery smooth muscle cells is enhanced. The results showed that CBD (GM-CSF). Pre-treatment with a PPARγ antagonist suppressed the in­
exposure restored the aberrant pathological findings in Sugen-hypoxia duction of MDSC by CBD. It was concluded that CBD activated PPARγ in
and monocrotaline-induced PAH mice models independent of PPARγ the mast cells to elevate secretion of G-CSF and, subsequently, MDSC
activation (Lu et al., 2021). The previously mentioned findings suggest mobilization. Using the luciferase reporter assay, the researchers indi­
an active role for PPARγ in CBD interaction with the cardiovascular cated that CBD increased the transcriptional activity of PPARγ (Hegde

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Table 1
A summary of CBD-mediated effects via PPARγ in various in vitro and in vivo models.
Concentration/Dose of Model/Target CBD’s effect PPARγ antagonist’s effect Reference
CBD/Intervention
9 7
10 − to 10 − M SHSY5Y and SHSY5YAPP+ cells CBD induced the ubiquitination of APP protein, The effects of CBD were prohibited (Scuderi et al., 2014)
decrease Aβ production, reduced apoptosis by GW9662 as a PPARγ antagonist
− 9 − 7
10 to 10 M 10 mg/ Rat primary astroglia Male CBD reduced NO, TNF-α, IL-1β, and Aβ-induced The effects of CBD were inhibited (Esposito et al., 2011)
kg (Intraperitoneal, 15 Sprague-Dawley rats up-regulation of iNOS, GFAP, S100B via NF-κB by GW9662
days) inhibition, rescued CA1 pyramidal neurons
integrity, reduced gliosis, and restored
neurogenesis in the dentate gyrus
10 µM Hippocampal slices from C57BL/ CBD attenuated Aβ-mediated deficits in LTP The effect of CBD was suppressed (Hughes and Herron,
6 mice by GW9662 2019)
10 and 30 pmol (Intra- Male Wistar rats CBD impaired memory consolidation when CBD effect given one hour after fear (Raymundi et al.,
dorsal hippocampus, given immediately or 1 h after fear conditioning conditioning was suppressed by 2020)
single dose) GW9662
15, 30, and 60 mg/kg Male adult C57BL/6 mice CBD, when combined with capsazepine, as a Administration of GW9662 (Dos-Santos-Pereira
(Intraperitoneal, single TRPV1 antagonist, reduced abnormal diminished axial abnormal et al., 2016)
dose) involuntary movements involuntary movements
10 µM 60 mg/kg Primary microglial cultures Male CBD reduced LPS-induced microglia activation, The effects of CBD were suppressed (Sonego et al., 2018)
(Intraperitoneal, single Swiss mice decreased NF-κB translocation, oxidative stress, by GW9662
dose) vacuos chewing movements
60 mg/kg Male Swiss mice CBD decreased haloperidol-induced orofacial The effects of CBD were prevented (Sonego et al., 2021)
(Intraperitoneal, for 7 dyskinesia and increased the discrimination by GW9662
days) index in the novel object recognition test
5 mg/kg Female SJL/J mice as a viral CBD treatment improved motor deficits The effect of CBD was suppressed (Feliú et al., 2015)
(Intraperitoneal, single model of MS by T0070907, as a PPARγ
dose) antagonist
10 mg/kg Male C57BL/6 mice with CBD reduced IFN-γ and IL-17, promoted – (Giacoppo et al., 2017)
(Intraperitoneal, single experimental autoimmune neuronal survival, and up-regulated PPARγ
dose) encephalomyelitis
10 mg/kg Male C57BL/6 J mice with CBD suppressed anxiety-like behaviors, memory The effects of CBD were suppressed (Mori et al., 2021)
(Intraperitoneal, single bilateral common carotid artery impairment, and despair-like behaviors by GW9662
dose) occlusion
12 and 120 mg/kg Rat model of temporal lobe CBD decreased total seizure duration and CBD increased PPARγ level in the (Costa et al., 2022)
(Subcutaneous, 3 days, epilepsy occurrence and 50% of rats were seizure free hippocampal CA3 subfield,
BID) amygdala, and perirhinal cortex
10 − 9 to 10 − 5 M and 10 Isolated human pulmonary CBD promoted a full concentration- and time- The effect of CBD was blocked by (Baranowska-Kuczko
μM arteries (hPAs) and rat small dependent vasorelaxation GW9662 et al., 2020)
mesenteric arteries (Wistar)
1–30 μM Male Wistar rats Human CBD induced vasorelaxation of aorta, increased The effects of CBD were suppressed (O’Sullivan et al.,
embryonic kidney (HEK293) the transcriptional activity of PPARγ, bound to by GW9662 2009)
cells and 3T3L1 fibroblasts PPARγ and stimulate the differentiation of 3T3-
L1 fibroblasts into adipocytes
10 μM Human brain microvascular CBD reduced BBB permeability, VCAM-1, and The effects of CBD were prevented (Hind et al., 2016)
endothelial cells (HBMECs) VEGF) by GW9662
50 mg/kg Male Wistar rats with CBD showed beneficial effects on weight bearing GW9662 prevented weight bearing (Mlost et al., 2021)
(Intraperitoneal, for 2 experimental osteoarthritis and pain but did not affect heat or
days) mechanical hypersensitivity
1, 10, and 20 mg/kg Female C57BL/6 mice Female CBD triggered substantial induction of BADGE as a PPARγ antagonist (Hegde et al., 2015)
(Intraperitoneal, single vanilloid receptor knockout mice CD11b+Gr-1+ MDSC, induced G-CSF, CXCL1, suppressed the induction of MDSC
dose) and mast cell-deficient mice and M-CSF and enhanced the transcriptional by CBD
activity of PPARγ
10 − 8 to 10 − 6 M 10 mg/ Rectal mucosal samples from CBD alleviated reactive enteric gliosis, reduced GW9662 the effects of CBD on (De Filippis et al.,
kg (Intraperitoneal, normal rectal Intestinal S100B, TNF-α, and cleaved caspase-3 CBD S100B and iNOS proteins and nitric 2011)
single dose) segments of male Swiss OF1 mice treatment in rectal biopsies of patients with oxide
ulcerative colitis decreased S100B and iNOS
proteins
9 7
10 − to 10 − M Caco-2 cells exposed to SARS- CBD decreased RhoA-GTPase, NLRP3, TLR-4, The effects of CBD were suppressed (Corpetti et al., 2021)
CoV-2 spike protein ACE-2, caspase-1, IL-1β, IL-6, TNF-α, and IL-18. by GW9662
3 μM Subcutaneous adipose sample CBD suppressed cell proliferation, IL-6 release, Selective PPAR-γ agonist (Ruhl et al., 2018)
lipid and protein oxidation, and promoted rosiglitazone restored LPS
adipogenic as well as chondrogenic inhibition of adipogenesis
differentiation
10 μM 1 and 5 mg/kg Caco-2 and HCT116 human CBD decreased aberrant crypt foci, polyps, and The effect of CBD on proliferation (Aviello et al., 2012)
(Intraperitoneal, single colon adenocarcinoma cell lines tumors, prevented changes in phospho-Akt and in cell culture was suppressed by
dose) Male ICR mice caspase-3 ratio, protected DNA against oxidative GW9662
stress, and decreased cell proliferation
1 and 3 μM A549 and H460 human lung CBD increased COX-2 and PPARγ mRNA and The tumor-regressive effect of CBD (Ramer et al., 2013)
carcinoma cells protein levels in A549 and H460 cells, in athymic nude mice xenografted
translocated PPARγ to the nucleus, and with A549 cells was prevented by
promoted an apoptotic cell death GW9662
10 μM ME-180 cervical cancer cell line CBD induced apoptosis of cervical cancer cell The effect of CBD was suppressed (Bagavandoss et al.,
line by GW9662 2016)
0.001–100 μM hTERT immortalized adipose CBD promoted the differentiation of MSCs, The effect of CBD on adipogenesis (Chang et al., 2022)
derived mesenchymal stem cells induced adipogenesis and enhanced FSP27, was prohibited by T0070907
FABP4, and PPARG2 as adipogenic genes
(continued on next page)

6
S. Khosropoor et al. Phytomedicine 114 (2023) 154771

Table 1 (continued )
Concentration/Dose of Model/Target CBD’s effect PPARγ antagonist’s effect Reference
CBD/Intervention

1, 5, and 10 μM 3T3-L1 cells CBD up-regulated brown fat markers including The effect of CBD on brown (Parray and Yun, 2016)
the PGC-1α, UCP1, PPARγ, and PRDM16, adipogenesis was suppressed by
GW9662

et al., 2015). Cannabinoids induce various effects on the intestinal sys­ epithelial injury and inflammatory response induced by SARS-CoV-2
tem. The effect of cannabinoids on intestinal permeability was investi­ spike protein (SP) in Caco-2 cells was investigated (Corpetti et al.,
gated by Alhamoruni et al. (Alhamoruni et al., 2010). The results 2021). CBD decreased various pro-inflammatory markers following SP
indicated that Δ9-THC and CBD enhanced the speed of recovery of exposure, such as family members of Ras homologues A-GTPase
ethylenediaminetetraacetic acid-induced increased permeability in the (RhoA-GTPase), NLR family pyrin domain containing 3 (NLRP3),
apical and basolateral membranes of Caco-2 cells. This effect of CBD was Toll-like receptor 4 (TLR4), angiotensin-converting enzyme 2 (ACE-2),
mediated by CB1 but not CB2, TRPV1, or PPARγ receptors (Alhamoruni and caspase-1. It also diminished IL-1β, IL-6, TNF-α, and IL-18. These
et al., 2010). Enteric glial cells (EGC) have been reported to mediate effects were prevented by a PPARγ antagonist. CBD increased the
inflammation in the gut. They release pro-inflammatory cytokines, expression of tight-junction proteins, restored transepithelial electrical
neurotrophins, and growth factors that affect the immune response. resistance, and rescued fluorescein isothiocyanate (FITC)-dextran
They serve as a key link between the nervous and immune systems in the permeability triggered by SP. These findings showed that CBD served as
intestine. The CBD effects on intestinal samples from patients having an efficient inhibitor of SP protein enterotoxicity. So, it was concluded
ulcerative colitis (UC) and intestinal biopsies of mice with experimental that CBD, via activation of PPARγ, ACE-2 expression suppression, and
intestinal inflammation were investigated. CBD treatment alleviated down-regulation of RhoAGTPase/NLRP3/caspase-1 pathway, could
reactive enteric gliosis in mice with intestinal inflammation via S100B prevent viral entry and replication in the intestine (Corpetti et al., 2021)
reduction. CBD also substantially decreased TNF-α and cleaved (Fig. 3). However, in contrast to previously mentioned findings
caspase-3 expressions and mast cell and macrophage presence in the regarding the anti-inflammatory and preventive effects on virus entry,
intestine. CBD treatment of the rectal biopsies of patients with UC daily administration of CBD (300 mg) did not modify the mild to mod­
reversed the elevated levels of S100B and iNOS proteins. These effects, erate symptoms of COVID-19 (Crippa et al., 2022).
plus nitric oxide production were blocked by a PPARγ antagonist,
implying the important role of PPARγ during intestinal inflammation CBD and PPARγ interaction in cancer
(De Filippis et al., 2011).
The effect of CBD on an experimental model of osteoarthritis showed Successful treatment of cancer remains one of the major problems of
that CBD might have beneficial effects on this disease (Mlost et al., human health. Many studies show that CBD has beneficial effects on
2021). The results indicated that, in contrast to the TRP channel an­ cancer cells both in vitro and in vivo. CBD exhibited anti-proliferative
tagonists, administration of GW9662, a PPARγ antagonist, prevented the properties against colon, breast, cervix, glioma, prostate, ovary, leuke­
positive effect of CBD on weight-bearing, but did not affect heat or mia, and thyroid cancer cells (Massi et al., 2013). The main mechanisms
mechanical hypersensitivity (Mlost et al., 2021). Mesenchymal stromal underlying the anticancer effects of CBD are inhibition of intercellular
cells (MSCs) act similarly to inflammatory macrophages and release adhesion molecule-1 (ICAM-1)-dependent cell invasion, reduction in
transforming growth factor β (TGF-β), IL-10, IL-6, and IL-7 (Shi et al., epidermal growth factor (EGF)-induced cell migration, AMP-activated
2018). Prolonged TLR4 stimulation promotes MSC osteogenic differen­ protein kinase (AMPK), Akt, and plasminogen activator inhibitor-1
tiation and proliferation while reducing adipogenic differentiation and (PAI-1) inhibition, intracellular Ca2+, COX-2, and PPARγ enhance­
cellular and metabolic activity (Fiedler et al., 2013). The ment, autophagy inhibition, apoptosis induction, and ROS generation.
anti-inflammatory potential of CBD on MSC1 was investigated on These effects were mediated via CB1, CB2, TRPV1, GPR55, and PPARγ
LPS-stimulated adipose tissue MSCs (Ruhl et al., 2018). The results (Heider et al., 2022) (see Fig. 4). However, we specifically mentioned
indicated that LPS exposure enhanced cell proliferation, IL-6 release, those studies in which the role of PPARγ was investigated. Aviello et al.
lipid and protein oxidation, and inhibited adipogenic and chondrogenic evaluated the effect of CBD on azoxymethane-induced colon cancer in
differentiation. These effects were suppressed in the presence of CBD. mice. Azoxymethane treatment increased aberrant crypt foci, polyps,
Using a PPARγ agonist, the researchers concluded that the effects of CBD tumor formation, up-regulated phospho-Akt, COX-2, and iNOS, and
on adipogenic and chondrogenic differentiation were presumably reduced cleaved caspase-3/caspase-3 ratio. CBD treatment could
mediated via activation of PPARγ (Ruhl et al., 2018). decrease aberrant crypt foci, polyps, and tumors and prevent changes in
phospho-Akt and caspase-3 ratio. Using colorectal carcinoma cell lines,
CBD and PPARγ interaction in viral infections the researchers revealed that CBD induced a significant protective effect
on DNA against oxidative stress, decreased cell proliferation, and
In recent years, CBD has received more attention as an antiviral elevated endocannabinoid levels that were mediated via PPARγ, TRPV1,
agent. It has an antiviral effect on Kaposi’s sarcoma-associated herpes and CB1 receptors implying multiple targets in the chemopreventive
virus (Maor et al., 2012) and hepatitis C virus, but not on hepatitis B effect of CBD against colon cancer (Aviello et al., 2012). The contribu­
virus (Lowe et al., 2017). CBD’s anti-inflammatory and analgesic tion of PPARγ to the pro-apoptotic property of CBD has been investi­
properties make it plausible for use in oral and genital herpes, shingles, gated in human lung cancer cells. The study findings indicated that CBD
and Ebola (Mabou Tagne et al., 2020). CBD also potentiated the antiviral increased COX-2 and PPARγ mRNA and protein levels in A549 and H460
effects of terpenes against human Coronavirus E229 (Chatow et al., cells. CBD also up-regulated prostaglandin E2 (PGE2), PGD2, and
2021). A second study demonstrated significant antiviral effects of CBD 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) via COX-2 and
combined with terpenes against SARS-CoV-2 (Santos et al., 2022). resulted in the translocation of PPARγ to the nucleus, promoting
COVID-19 is a viral disease with significant inflammatory reactions PPARγ-dependent apoptotic cell death. Further experiments showed
in the body. It has a high morbidity and mortality rate, and many people that applying COX-2 and PPARγ inhibitors suppressed CBD-induced
in various countries died in 2021 during the epidemic. This virus causes DNA fragmentation and loss of viability in A549 and H460 cells
an aberrant release of pro-inflammatory molecules and may result in a (Ramer et al., 2013) (Fig. 3). The researchers also showed that CBD
cytokine storm that features a poor prognosis. The effect of CBD against promoted a tumor-regressive effect in athymic nude mice xenografted

7
S. Khosropoor et al. Phytomedicine 114 (2023) 154771

Fig. 3. A schematic illustration of PPARγ-mediated effects of CBD.

15d-PGJ2: 15-deoxy-delta-12,14-prostaglandin J2, Aβ: amyloid beta, CBD: cannabidiol, COX-2: cyclooxygenase-2, CXCL1: C-X-C motif chemokine ligand 1, GFAP:
glial fibrillary acidic protein, GSK-3β: glycogen synthase kinase-3β, IL-1β: interleukin 1β, IL-16: interleukin 6, IL-18: interleukin 18, iNOS: inducible nitric oxide
synthase, NLRP3: NLR family pyrin domain containing 3, NF-κB: nuclear factor kappa B, PGD2; prostaglandin D2, PGE2: prostaglandin E2, ROS: reactive oxygen
species, RXR: retinoid X receptor, TLR4: Toll-like receptor 4, TNF-α: tumor necrosis factor-α, VCAM-1: vascular cell adhesion molecule 1, Wnt: wingless-related
integration site.

with A549 cells that was prevented by a PPARγ inhibitor, implying the and cold allodynia that were suppressed by a PPARγ antagonist but not a
vital role of PPARγ in the anti-tumor effect of CBD (Ramer et al., 2013). CB1 or CB2 receptor antagonist (Silva et al., 2022).
Similar to the previous studies, the anti-proliferative effect of CBD on the
ME-180 cervical cancer cell line was exploited. CBD induced remarkable CBD and PPARγ interaction in adipogenesis
apoptosis of the cervical cancer cell line that was reversed by a PPARγ
antagonist and partially by a CB1 antagonist. However, the cytoplasmic PPARγ has a crucial role in white adipose tissue adipogenesis and is
vacuoles observed in the presence of CBD did not vanish following considered a “master regulator” of adipogenesis (Wafer et al., 2017).
exposure to either compound (Bagavandoss et al., 2016). In mammalian Mutations within the PPARγ gene have been associated with severe
cells, cytoplasmic vacuolization is a morphological process caused by lipodystrophy, insulin resistance, and diabetes in humans (Agostini
bacteria and viruses, as well as by chemicals. Its role in cell death is et al., 2006). Considering the crucial role of PPARγ in adipogenesis, the
unclear but often accompanies cell death (Shubin et al., 2016). These effect of CBD on adipogenesis in human and mouse multipotent MSCs
results suggest that CBD can potentially be used to treat cervical cancer. was assessed. The results revealed that CBD promoted the differentiation
Chemotherapy-induced peripheral neuropathy (CIPN) is a major of MSCs and induced adipogenesis that was prevented by a PPARγ
adverse effect of chemotherapy. Inflammation has a key role during antagonist. Co-treatment of CBD with rosiglitazone intensified the ef­
CIPN (Brandolini et al., 2019). Controlling CIPN enhances patient fects of CBD on adipogenesis. CBD also induced adipogenic genes such as
compliance and adherence to the drug treatment protocol. Paclitaxel FSP27, FABP4, and PPARG2. It promoted a stronger adipogenic response
(PTX) is an important chemotherapeutic agent that causes substantial in human adipose-derived MSCs than in mouse MSCs (Chang et al.,
molecular and cellular damage in the peripheral nervous system elicit­ 2022). Literature data show that persons with adipocyte-related meta­
ing peripheral neuropathies. The effect of 4′ -Fluorocannabidiol bolic dysfunctions have a different adipogenic function of adipose stem
(PECS-101), a CBD fluorinated analog, on PTX-induced neuropathic cell subpopulations, primarily bone marrow-derived mesenchymal stem
pain in mice was investigated (Silva et al., 2022). PECS-101 has more cells (BM-MSCs). Subsequent events are increased risk of diabetes, heart
anxiolytic- and antidepressant-like effects than CBD (Breuer et al., attack, or stroke (Shin et al., 2020). So, MSCs are deemed therapeutic
2016). Co-administration of PECS-101 with PTX prevented mechanical targets for restoring tissue and metabolism homeostasis in the adipose.

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S. Khosropoor et al. Phytomedicine 114 (2023) 154771

Fig. 4. A schematic illustration of CBD’s anti­

cancer effect.
CBD promotes autophagic cell death, apoptosis,
and oxidative stress while reducing cancer cell
invasion. CAT: catalase, COX-2: cyclo­
oxygenase-2, EGF: epidermal growth factor,
EGFR: epidermal growth factor receptor, ERα:
estrogen receptors alpha, GPx: glutathione
peroxidase, GSSG: oxidized glutathione, ICAM-
1: intercellular adhesion molecule-1, MDA:
malondialdehyde, Nrf2: nuclear factor
erythroid 2–related factor 2, p38 MAPK: p38
mitogen-activated protein kinases, PAI-1: plas­
minogen activator inhibitor-1, PPARγ: peroxi­
some proliferator-activated receptor gamma,
ROS: reactive oxygen species, TIMP-1: Tissue
inhibitor matrix metalloproteinase 1, mTOR:
mammalian target of rapamycin.

The effect of systemic administration of CBD on viability, proliferation, diseases (de la Monte and Wands, 2006). PPARγ agonists are a class of
and differentiation of BM-MSCs isolated from female mice was investi­ anti-diabetic drugs whose applications are beyond their
gated (Fellous et al., 2020). CBD provoked differentiation in BM-MSCs glucose-lowering effects; breast cancer (Yee et al., 2007), rheumatoid
that was comparable with rosiglitazone, an agonist of PPARγ. The ef­ arthritis (Ormseth et al., 2013), high blood pressure (Piché et al., 2018),
fect of CBD on mRNA expression of the PPARγ2 gene and its downstream endothelial function (Shi et al., 2010), hepatocellular carcinoma (Wal­
signaling targets, CCAAT/enhancer binding protein alpha (C/Ebpα) and ter et al., 2017), drug craving (Schmitz et al., 2017), AD (Sato et al.,
fatty acid binding protein 4 (Fabp4) was investigated. The results 2011), and depression (Kemp et al., 2014). This wide range of biological
showed that CBD enhanced PPARγ2, C/Ebpα, and Fabp4 gene expression effects implies that PPARγ activation influences multiple intracellular
(Fellous et al., 2020). Several lines of evidence indicate that white adi­ targets. So, natural compounds, via activating this receptor, have the
pocytes contain a single large lipid droplet and are involved in energy potential to induce diverse pharmacological effects.
storage. In contrast, brown adipocytes in brown fat are filled with CBD, a natural compound with diverse molecular targets, is an
multiple tiny lipid droplets and mitochondria. They facilitate heat interesting molecule to consider as a therapeutic agent. So, finding its
generation from stored energy via uncoupling protein 1 (UCP1) (Shin targets will help us understand its actions and potential applications.
et al., 2020). CBD effects on the brown fat-like phenotype in 3T3-L1 cells The present review article shows that PPARγ is an important target for
showed that it could up-regulate brown fat markers, including PGC-1α, CBD, which mediates part of its biological actions. For example, CBD
UCP1, PPARγ, and PRDM16, dose-dependently (Parray and Yun, 2016). induces protective effects against experimental models of anxiety,
The protein expression of phosphoinositide 3-kinases (PI3K) was also depression, movement abnormalities, MS, and AD via PPARγ activation.
up-regulated. Treating cells with either a PPARγ inhibitor or a PI3K FDA approval of Epidiolex® and the recent legalization of com­
inhibitor in 3T3-L1 adipocytes blocked brown adipogenesis. So, it was mercial hemp in many countries, plus the safety and tolerability of CBD
concluded that CBD, via activating PPARγ and PI3K signaling, promoted in clinical practice (McCartney et al., 2022; O’Brien et al., 2022) have
brown adipogenesis (Parray and Yun, 2016). Considering the crucial led to enhanced interest in CBD-based treatments in recent years (Rapin
role of PPARγ in adipogenesis, CBD can induce significant effects in et al., 2021). In accordance with the experimental studies, the thera­
adipocytes that may help resolve some metabolic abnormalities. peutic potential of CBD as an add-on therapy in the treatment of anxiety
(Berger et al., 2022), PTSD (Das et al., 2013), psychosis (Devinsky et al.,
Conclusion and perspectives 2014), cognitive dysfunction (McCartney et al., 2022), dementia (Kło­
sińska and Leszko, 2022), and epilepsy (Pesántez Ríos et al., 2022) has
PPARγ receptors are attractive drug targets as they modulate various been indicated in clinical studies. Topical CBD has been used to treat
physiological processes. They may offer a promising target for treating peripheral neuropathy (Xu et al., 2020). In addition, CBD increases
diseases such as AD due to their variable expression during selected glucose-dependent insulinotropic peptide (GIP) and decreases resistin in

9
S. Khosropoor et al. Phytomedicine 114 (2023) 154771

type 2 diabetic patients (Jadoon et al., 2016), suggesting that it has the PPARγ/CB2 agonists or γ-secretase/PPARγ modulators have been
potential to suppress obesity and insulin resistance as the underlying developed for treating the systemic sclerosis (García-Martín et al., 2019)
abnormalities for many secondary diseases. More recently, experimental and Alzheimer’s disease, respectively (Hieke et al., 2010). The use of
studies show that CBD reduces weight gain and liver injuries in PPARγ ligands on cancer cells is reported with controversies as they may
diet-induced obesity (Han et al., 2022; Jiang et al., 2021). The present increase or decrease cancer cell proliferation (Yousefnia et al., 2018).
review also showed that the effects of CBD on the immune system, So, we suggest that the significant anticancer effect of CBD may reduce
cancer, vasculature, and adipose tissue were mediated, at least, partially the concerns regarding the tumorigenic effects of PPARγ ligands. Alto­
via PPARγ activation. Previous studies show that CBD and Δ9-THC act as gether, the present article highlights the role of PPARγ among diverse
full agonists of PPARγ (Fishbein-Kaminietsky et al., 2014; Mlost et al., molecular targets of CBD. Many effects of CBD are mediated via inter­
2021). However, some other natural cannabinoids from Cannabis sativa, action by PPARγ. In future CBD studies, we recommend that this inter­
such as cannabigerolic acid, cannabidiolic acid, and cannabigerol have action be taken into account.
been reported as PPARγ partial agonists (Iannotti and Vitale, 2021). The
effects of CBD on PPARγ expression have been reported with contro­ CRediT authorship contribution statement
versies; it may enhance PPARγ expression (Hegde et al., 2015; O’Sulli­
van et al., 2009) or decrease PPARγ expression (Mlost et al., 2021). It Ali Roohbakhsh: Conceptualization. Sara Khosropoor and
was indicated that CBD effects are completely subject-dependent. For Mohaddeseh Sadat Alavi: Writing the original draft. Leila Etemad and
example, the vasorelaxant effect of CBD is reduced in overweight, Ali Roohbakhsh: Writing– review & editing. All authors have read and
hypercholesteremic, diabetic, and hypertensive patients (Bar­ approved the final version of the manuscript. All data were generated in-
anowska-Kuczko et al., 2020; Stanley et al., 2015). This finding may be house, and no paper mill was used. All authors agree to be accountable
explained by a lower PPARγ expression during these conditions (Ame­ for all aspects of work ensuring integrity and accuracy.
shima et al., 2003; Catalano et al., 2002). Another explanation for the
lower effects of CBD via PPARγ activation is the concomitant expression
Declaration of Competing Interest
of active molecules with opposite action(s). For example, it was reported
that elevated expression of various TRP channels demasked
The authors declare no competing interest.
CBD-induced heat hyperalgesia (Mlost et al., 2021). Such interaction
may also justify the weak or contradictory findings in some studies.
Acknowledgment
Another reason for the lack of PPARγ-mediated effects has been attrib­
uted to its tissue-specific effects. In accordance, the lack of
The authors appreciate Mashhad University of Medical Sciences for
PPARγ-mediated vasorelaxation was attributed to the size of the arteries
financial support.
(Stanley et al., 2015). Some studies have offered a time-dependent effect
for CBD. For instance, CBD induced time-dependent (over two hours)
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