Antiseizure Effects of Cannabidiol Leading to Increased Peroxisome Proliferator-Activated Receptor Gamma Levels in the Hippocampal CA3 Subfield of Epileptic Rats

Costa, Anna-Maria; Russo, Fabiana; Senn, Lara; Ibatici, Davide; Cannazza, Giuseppe; Biagini, Giuseppe

doi:10.3390/ph15050495

Cited by 16 publications

(10 citation statements)

References 40 publications

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“…The transient receptor potential vanilloid type 1 (TRPV1) was shown to mediate the anti-seizure effects of CBD in the maximal electroshock model [ 37 ], and heterozygous deletion of Trpv1 was proconvulsant against hyperthermia-induced seizures in Scn1a +/- mice [ 38 ]. Recent evidence also suggests that CBD might work through the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), as the anti-seizure effects of CBD was associated with increased hippocampal PPARγ expression in a rat model of temporal lobe epilepsy [ 39 ]. It may also be that the anti-seizure effect of CBD is not mediated by interaction with one drug target, but that it requires a simultaneous action on a variety of targets.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous deletion of Gpr55 does not affect a hyperthermia-induced seizure, spontaneous seizures or survival in the Scn1a+/- mouse model of Dravet syndrome

et al. 2023

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A purified preparation of cannabidiol (CBD), a cannabis constituent, has been approved for the treatment of intractable childhood epilepsies such as Dravet syndrome. Extensive pharmacological characterization of CBD shows activity at numerous molecular targets but its anticonvulsant mechanism(s) of action is yet to be delineated. Many suggest that the anticonvulsant action of CBD is the result of G protein-coupled receptor 55 (GPR55) inhibition. Here we assessed whether Gpr55 contributes to the strain-dependent seizure phenotypes of the Scn1a+/- mouse model of Dravet syndrome. The Scn1a+/- mice on a 129S6/SvEvTac (129) genetic background have no overt phenotype, while those on a [129 x C57BL/6J] F1 background exhibit a severe phenotype that includes hyperthermia-induced seizures, spontaneous seizures and reduced survival. We observed greater Gpr55 transcript expression in the cortex and hippocampus of mice on the seizure-susceptible F1 background compared to those on the seizure-resistant 129 genetic background, suggesting that Gpr55 might be a genetic modifier of Scn1a+/- mice. We examined the effect of heterozygous genetic deletion of Gpr55 and pharmacological inhibition of GPR55 on the seizure phenotypes of F1.Scn1a+/- mice. Heterozygous Gpr55 deletion and inhibition of GPR55 with CID2921524 did not affect the temperature threshold of a thermally-induced seizure in F1.Scn1a+/- mice. Neither was there an effect of heterozygous Gpr55 deletion observed on spontaneous seizure frequency or survival of F1.Scn1a+/- mice. Our results suggest that GPR55 antagonism may not be a suitable anticonvulsant target for Dravet syndrome drug development programs, although future research is needed to provide more definitive conclusions.

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Section: Discussionmentioning

confidence: 99%

Heterozygous deletion of Gpr55 does not affect a hyperthermia-induced seizure, spontaneous seizures or survival in the Scn1a+/- mouse model of Dravet syndrome

et al. 2023

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“…20 In an animal model of TLE, the antiseizure effects of CBD are concomitant with an increase in the hippocampal levels of PPARγ, whereas inhibition of PPARγ leads to higher excitability levels and excitotoxicity. 21 CBD has been approved by the US Food and Drug Association (FDA) for the treatment of children with Dravet and Lennox-Gastaut syndromes, two types of rare epileptic encephalopathies. 22 Recently, cannabidiol has also been approved by the FDA for treating epilepsy in tuberous sclerosis complex.…”

Section: Phyto Can Nab Ino Ids and Epilepsymentioning

confidence: 99%

“…CBD (and other exo‐/endocannabinoids) can also activate peroxisome proliferator‐activated receptor γ (PPARγ), a nuclear hormone receptor that regulates gene transcription 20 . In an animal model of TLE, the antiseizure effects of CBD are concomitant with an increase in the hippocampal levels of PPARγ, whereas inhibition of PPARγ leads to higher excitability levels and excitotoxicity 21 …”

Section: Phytocannabinoids and Epilepsymentioning

confidence: 99%

Cannabinoid regulation of neurons in the dentate gyrus during epileptogenesis: Role of CB1R‐associated proteins and downstream pathways

et al. 2023

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The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus.After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies.

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“…PPARγ could also be involved in the modulation of the anticonvulsant effects of EP-80317, a ghrelin receptor antagonist [ 24 ]. Finally, the antiseizure effects of cannabidiol were associated with the upregulation of PPARγ in the hippocampal CA3 region [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies

et al. 2023

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Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold—the PPAR agonists (1a (αEC50 1.0 μM) and 1b (γEC50 0.012 μM)) and antagonists (2a (αIC50 6.5 μM) and 2b (αIC50 0.98 μM, with a weak antagonist activity on γ isoform))—on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1–10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.

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Antiseizure Effects of Cannabidiol Leading to Increased Peroxisome Proliferator-Activated Receptor Gamma Levels in the Hippocampal CA3 Subfield of Epileptic Rats

Cited by 16 publications

References 40 publications

Heterozygous deletion of Gpr55 does not affect a hyperthermia-induced seizure, spontaneous seizures or survival in the Scn1a+/- mouse model of Dravet syndrome

Heterozygous deletion of Gpr55 does not affect a hyperthermia-induced seizure, spontaneous seizures or survival in the Scn1a+/- mouse model of Dravet syndrome

Cannabinoid regulation of neurons in the dentate gyrus during epileptogenesis: Role of CB1R‐associated proteins and downstream pathways

Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies

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