Activation of the Cannabinoid Receptors Suppresses Hyperexcitation of Rat Hippocampal Neuronal Networks In Vitro

Abstract

Cannabinoid receptors (CBRs) play a key role in various physiological processes, including neurogenesis, synaptic plasticity, immune modulation, cell apoptosis, metabolism regulation, cardiovascular and reproductive systems activity. Since activation of CBRs suppresses hyperexcitation and protects cells from death, their modulation may have therapeutic prospects in the treatment of such pathologies of the nervous system as mental disorders, epilepsy, Parkinson’s and Huntington’s disease, multiple sclerosis, spinal cord and brain injuries. This paper presents experimental data on the effects of the cannabinoid receptor agonist WIN 55,212-2 on the induced oscillations of intracellular Ca²⁺ concentration ([Ca²⁺]_i) in two in vitro models of epileptiform activity. To study the neuroprotective properties of WIN 55,212-2, hyperexcitation was induced by the application of a GABA(A) receptor antagonist, bicuculline, or depolarizing doses of ammonium chloride. As experiments have shown, WIN 55,212-2 at a concentration of 100 nM and above significantly suppresses the [Ca²⁺]_i oscillations frequency and reduces the basal [Ca²⁺]_i level. At the same time, the amplitude of calcium oscillations also decreased in the presence of the agonist. WIN 55,212-2 at a concentration of 2 μM suppressed NH₄Cl-induced [Ca²⁺]_i oscillations in all neurons but caused a transient biphasic increase in the basal [Ca²⁺]_i level in 20% of astrocytes. Thus, in this work, using various models of hyperexcitation of neuronal networks, we have demonstrated a potential antiepileptic effect of the cannabinoid receptor agonist WIN 55,212-2.