Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

Abstract

γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.

The Transcriptomic Analysis of NSC-34 Motor Neuron-Like Cells Reveals That Cannabigerol Influences Synaptic Pathways: A Comparative Study with Cannabidiol

“…On the contrary, CBD is known to be involved in the regulation of the excitatory transmission of glutamate and the inhibitory transmission of GABA [ 25 ]. In particular, CBD appears to be a GABA A receptor modulator, being able to increase GABA-evoked currents [ 26 ].…”

Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease

“…This receptor binds three classes of type A receptor: GABA A , GABA B and GABA C . Among these, the GABA A receptor subfamily appears to be involved in many neurological diseases [123][124][125]. Deficits of this receptor are responsible for several neurological disorders such as Huntington's disease [126], cognitive alterations [3], epileptic disorders [127], drug addiction [128], chronic stress and anxiety [129].…”

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

“…Cannabis sativa is a plant that contains at least 104 cannabinoids identified until now, with different structure and different functional profile [ 35 ]. Two of these components form the majority and have been intensely studied in the last years: delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD).…”

“…Two of these components form the majority and have been intensely studied in the last years: delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Other compounds such as cannabinol (CBN), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabichromene (CBC), cannabielsoic acid A, cannabicyclol (CBL), Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and Δ9-tetrahydrocannabivarin (Δ9-THCV) form the minority of phytocannabinoids found in Cannabis sativa plant [ 35 ].…”