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Positive allosteric modulation of type 1 cannabinoid receptors reduces spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg. | LitMetric

AI Article Synopsis

  • - Childhood Absence Epilepsy (CAE) affects about 10% of kids with epilepsy, but around one-third of patients don't respond well to current treatments, which can cause severe side effects like liver damage.
  • - Cannabinoids like CBD have potential in treating epilepsy, though their effectiveness for CAE is not yet proven, while a study shows how THC increases seizure activity and CBD decreases it in a specific rat model (GAERS).
  • - Researchers noted that GAERS rats had lower levels of a receptor (CB1R) and higher endocannabinoid levels; administering positive allosteric modulators (PAMs) of CB1R significantly reduced seizure-like activity, indicating a new pathway for potential CAE treatments.

Article Abstract

Childhood Absence Epilepsy (CAE) accounts for approximately 10% of all pediatric epilepsies. Current treatments for CAE are ineffective in approximately 1/3 of patients and can be associated with severe side effects such as hepatotoxicity. Certain cannabinoids, such as cannabidiol (CBD), have shown promise in the treatment of pediatric epilepsies. However, CBD remains limited or prohibited in many jurisdictions, and has not been shown to have efficacy in CAE. Modulation of the type 1 cannabinoid receptor (CB1R) may provide more desirable pharmacological treatments. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of CAE, including cortical spike and wave discharges (SWDs). We have recently demonstrated that Δ-tetrahydrocannabinol (THC) increases SWDs in GAERS whereas CBD decreases these events. Here, we characterized aspects of the endocannabinoid system in brain areas relevant to seizures in GAERS and tested whether positive allosteric modulators (PAMs) of CB1R reduced SWDs. Both female and male GAERS had reduced (>50%) expression of CB1R and elevated levels of the endocannabinoid 2-AG in cortex compared to non-epileptic controls (NEC). We then administered the CB1R PAMs GAT211 and GAT229 to GAERS implanted with cortical electrodes. Systemic administration of GAT211 to male GAERS reduced SWDs by 40%. Systemic GAT229 administration reduced SWDs in female and male GAERS. Intracerebral infusion of GAT229 into the cortex of male GAERS reduced SWDs by >60% in a CB1R-dependent manner that was blocked by SR141716A. Together, these experiments identify altered endocannabinoid tone in GAERS and suggest that CB1R PAMs should be explored for treatment of absence seizures.

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Source
http://dx.doi.org/10.1016/j.neuropharm.2021.108553DOI Listing

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