Abstract
Simple SummaryNeurodegenerative diseases represent an important cause of morbidity and mortality worldwide. Existing therapeutic options are limited and focus mostly on improving symptoms and reducing exacerbations. The endocannabinoid system is involved in the pathophysiology of such disorders, an idea which has been highlighted by recent scientific work. The current work focusses its attention on the importance and implications of this system and its synthetic and natural ligands in disorders such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis.Neurodegenerative diseases are an increasing cause of global morbidity and mortality. They occur in the central nervous system (CNS) and lead to functional and mental impairment due to loss of neurons. Recent evidence highlights the link between neurodegenerative and inflammatory diseases of the CNS. These are typically associated with several neurological disorders. These diseases have fundamental differences regarding their underlying physiology and clinical manifestations, although there are aspects that overlap. The endocannabinoid system (ECS) is comprised of receptors (type-1 (CB1R) and type-2 (CB2R) cannabinoid-receptors, as well as transient receptor potential vanilloid 1 (TRPV1)), endogenous ligands and enzymes that synthesize and degrade endocannabinoids (ECBs). Recent studies revealed the involvement of the ECS in different pathological aspects of these neurodegenerative disorders. The present review will explore the roles of cannabinoid receptors (CBRs) and pharmacological agents that modulate CBRs or ECS activity with reference to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and multiple sclerosis (MS).
Highlights
Neurodegenerative diseases are an increasing cause of global morbidity and mortality [1]
Increased levels of ECBs (AEA and 2-AG) in the brain through inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes are a successful therapeutic option for controlling the immune response in Alzheimer’s Disease (AD), Huntington’s Disease (HD) and multiple sclerosis (MS) disorders [12,68]. Several cellular mechanisms such as inhibition of both glutamate release at presynaptic level and NMDA-induced intracellular Ca2+ release, antioxidant activity, protein kinase A (PKA) signaling and nitric oxide generation contribute to the neuroprotective effect of type 1 cannabinoid receptors (CBRs) agonists on in vitro excitotoxicity, which is induced by N-methyl-D-aspartic acid (NMDA)
Numerous studies in animal models of Parkinson’s Disease (PD) have shown that pharmacological activation of CB2Rs suppressed the release of pro-inflammatory cytokines, selective agonists of CB2R with the ability to reduce inflammation in the brain of mice treated with MPTP, while pharmacological inactivation of these receptors resulted in reversal of this effect
Summary
Neurodegenerative diseases are an increasing cause of global morbidity and mortality [1]. The degenerative disorders are demonstrably affected by changes in their conformation, thereby gaining toxicity or losing physiological functions [14], and by inflammation [15] These diseases are the most commonly occurring forms and have fundamental differences regarding their underlying physiology and clinical manifestations, there are aspects that overlap, such as changes in the morphology of microglia, progressive neuronal loss, oxidative stress and elevated cytokine levels [16]. This complex cascade of underlying mechanisms shows that neurodegeneration as well as neuroinflammation play important roles in these types of disorders. The present review will explore the roles of CB1R and CB2R, and pharmacological agents that modulate CBRs or ECS activity, with reference to AD, PD, HD and MS diseases
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