Endocannabinoid System in Neurological Disorders

(Endocannabinoid System and Neurodegeneration)

Roberta Ranieri, Chiara Laezza, Maurizio Bifulco, Daniela Marasco and Anna Maria Malfitano

Recent Patents on CNS Drug Discovery, 2015, Vol. 10, No. 2, 24 p.

Abstract :

Background : Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

Methods : In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Results : Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Conclusion : Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.

Keywords : Endocannabinoid system, endocannabinoids, cannabinoid receptors, neurological disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease.

 

INTRODUCTION

Cannabis is constituted by numerous compounds, but its main component is delta 9-tetrahydro-cannabinol (delta9-THC) [1]. CB1 and CB2 receptors are selective cannabinoid receptors identified in neuronal and peripheral cells, respectively. THC mainly stimulates CB1 receptors that are found throughout the brain [2, 3]. After the identification of these receptors, endocannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG) have been detected in mammals and nervous tissues [4, 5], further, their synthetic and degrading enzymes have been also discovered [4, 6-9]. The endocannabinoid system
is composed of cannabinoid receptors, endocannabinoids and their synthetic and inactivating enzymes. Extensive research in the last decade has consolidated the view that endocannabinoids function throughout the central nervous system as powerful regulators of synapse by inhibiting transmitter release via transient or long-lasting mechanism [10-14]. In particular, the endocannabinoid that is produced by postsynaptic activity, goes backward throughout the synapse, binds the CB1 receptor and inhibits the production of neurotransmitters. Many lines of evidence also suggest a nonretrograde or autocrine signaling of endocannabinoids that modulate neural activity and synapse transmission via transient receptor potential vanilloid receptor type 1 (TRPV1). Furthermore, recent studies suggest a regulation of presynaptic or postsynaptic activity by endocannabinoids via astrocytes. Indeed, the endocannabinoid system has been suggested to affect synapse formation and neurogenesis [15]. It is also accepted that by controlling the synaptic strength, endocannabinoids can regulate neural activities like movement control, cognition, feeding and pain. Additionally, a dysregulated endocannabinoid system affects neuropsychiatric disorders like depression and anxiety [16, 17]. Thus, the endocannabinoid system represents an important therapeutic target [18, 19].

In pathologies like multiple sclerosis, Huntington’s, Parkinson’s and Alzheimer’s diseases, and amyotrophic lateral sclerosis, reports suggest symptomatic relief with cannabis. These observations suggest that an altered endocannabinoid system might be responsible for several symptoms. The finding that the CB1 receptor is highly expressed in areas of the brain like basal ganglia, cortex, cerebellum, hippocampus that affect cognition and motor function, further confirms the role of the endocannabinoid system in a variety of central nervous system disorders like neurodegenerative diseases. Numerous reports suggest the relevant role of the endocannabinoid system in neurological diseases like Alzheimer’s
disease, and Huntington’s disease [20, 21]. Several cannabinoid receptor dependent or independent activities contribute to the pathophysiology of these disorders, like antioxidant function of cannabinoids, stimulation of cytoprotective pathways (protein kinase A (PKA) and B (PKB)), and control of the immune response [22-27].

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