Epilepsy is a chronic neurological condition characterized by recurrent seizures and symptoms from simple momentary absences to violent convulsions lasting a few minutes. It is estimated that approximately 50 million people worldwide suffer from epilepsy and over 30% have drug-resistant epilepsy. The therapeutic use of Cannabis, and in particular of its non-psychotropic component CBD or cannabidiol,
has improved the quality of life of drug-resistant patients, showing excellent potential in reducing the frequency and severity of seizures.
Preventing the onset of the epileptic crisis and controlling the transition phase from the pre-symptomatic to the symptomatic state of disease is a crucial aspect of epileptogenesis. The availability of experimental animal models is of primary importance for understanding pathogenesis and drug testing.
Medicinal cannabis can provide advantages in the prevention and transition from the pre-epileptic to the epileptic phase, acting as a modulator of the “endocannabinoid system”, a class of small endogenous lipid mediators, able to regulate the excitability of neuronal networks.
Data from a study coordinated by Dr. Cristino at the CNR of Italy, Institue of Biomolecular Chemistry, reveal a new mechanism by which endocannabinoids reduce the number of seizures in certain forms of epilepsy resistant to pharmacological treatment.
The study exploited a genetic animal model of epilepsy, the Synapsin II knockout mice that are defective in the expression of the Synapsin II protein, a member of the multigene synapsin family playing a critical role in the control of neurotransmitter release.
Mutant mice lacking the SYN2 gene are all prone to developing spontaneous epileptic seizures after 2-3 months of age. The progressive increase in epileptic seizures makes this genetic model particularly interesting for studying the mechanisms of epileptogenesis and, above all, the transition from the pre- to the full-epileptic state.
By applying techniques for studying brain neurochemical signals such as electrophysiology, confocal microscopy, and behavioral tests, the study reveals how in this model brain development is associated with the loss of expression of the endocannabinoid CB1 receptor in the hippocampus together with the increase of glutamate release, an excitatory neurotransmitter promoting the onset of seizures in adult animals.
These results highlight how the regulation of the endocannabinoid system, and in particular of the expression of the mediator 2-Arachidonoylglycerol (2-AG), is essential in the balance between excitatory and inhibitory inputs in the hippocampus to maintain the stability of the neuronal networks and to prevent the onset and propagation of epileptic seizures.
This study published in the Cellular and Molecular Life Sciences (Forte et al., 2024; doi: 10.1007/s00018-023-05029-7), adds a new piece to the puzzle opening the way for the pharmacological approach to counteract epileptic encephalopathy in humans.
The study has been coordinated by Dr. Cristino at ICB, CNR of Pozzuoli, Italy, in collaboration with Prof. Di Marzo at Laval University of Canada, and coordinator of the International Research Unit between CNR and Canada (UMI-MicroMenu), with the research group of Prof. Benfenati at the University of Genoa, Italy and the ‘Italian Institute of Technology, and with Prof. De Girolamo at Federico II University of Naples.
