Effects of phytocannabinoids on Parkinson’s and Alzheimer’s disease

Neurodegenerative diseases leading to Parkinson's disease (PD) and Alzheimer's disease (AD) have become a major global health burden. Current treatments are mainly aimed at controlling symptoms, and there are no effective treatments in clinical practice to prevent neurodegeneration or induce neuronal repair. Therefore, the need for new research on these two diseases is urgent. The endocannabinoid system (ECS) is currently being studied as a drug target for PD and AD, where overexpression of ECS receptors has a neuroprotective effect in PD and reduces neuroinflammation in AD. Δ-9-tetrahydrocannabinoid (Δ9-THC) and cannabidiol (CBD) cannabinoids in the plant cannabis have shown neuroprotective effects in animal models of PD and AD.

Parkinson's disease and Alzheimer's disease

Neurodegenerative diseases (NDDs), characterized by the progressive atrophy of neurons in the central and peripheral nervous systems, have become a major disease burden not only in low- and middle-income countries (LMICs) but also in developed countries. Among all neurodegenerative diseases, Parkinson's disease (PD) accounts for 1.8% and Alzheimer's disease (AD) accounts for 12%, with higher reported prevalence in LMICs [1]. Therefore, the need for new research on these two diseases is urgent.

Parkinson's disease (PD) is the most common movement disorder and the second most common NDD[2]. It is characterized by the progressive death of dopaminergic neurons, primarily in the substantia nigra pars compacta (SNc), in the neostriatum, and to a lesser extent in the subthalamic nucleus of the basal ganglia. Genetic studies have shown that mutations in ubiquitin genes such as α-synuclein, PINKI, DJ-1 (PARK7), ubiquitin-c-hydrolase, and population-specific genes such as the glucocerebrosidase gene in Ashkenazi Jews[12] are directly associated with the onset of PD[3]. There is evidence that mutations in molecular signaling such as leucine-rich repeat kinase 2 (LRRK2) and Miro GTPases play a critical role in the onset and progression of PD.

Alzheimer's disease (AD) is the leading cause of dementia and the most common NDD, characterized by extracellular deposition of amyloid-β plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, as well as decreased levels of choline acetyltransferase [4].

Endocannabinoid system

Among the many molecular pathways involved in the pathophysiology of PD and AD, the endocannabinoid system (ECS) has attracted widespread attention in the past decade. With the realization that exogenous cannabinoid compounds such as cannabinoids extracted from the plant cannabis (also known as phytocannabinoids) can act on the brain's endocannabinoid system, the development of novel ECS-targeted therapeutic drugs has become a hot topic. The ECS of the central nervous system has multiple regulatory functions, including cognition, appetite control, and analgesia [5]. It is speculated that endocannabinoids regulate neuronal plasticity by regulating the enhancement, inhibition, and disinhibition of synaptic output, ultimately regulating synaptic function [6]. Although the exact molecular mechanism has not yet been elucidated, further research will help us understand the complex processes involved, including cognitive function, learning, and memory.

A recent study showed that Δ9-THC treatment of transgenic Tg4–42 mice overexpressing human Aβ4–42 resulted in reduced neuronal loss compared with controls [7]. In addition, a research study showed that THC can significantly reduce Aβ levels in cells, thereby exerting a neuroprotective effect on cells [8].

Literature has shown that the combined use of THC-CBD has a better neuroprotective effect than administration of either drug alone [9].

Reference:

[1]WHO (2018) Global burden of neurological disorders: estimates and projections neurological disorders: public health challenges, Geneva

[2]Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T (2016) The incidence of Parkinson’s disease: a systematic review and metaanalysis. Neuroepidemiology 46(4):292–300

[3]Polymeropoulos MH (2000) Genetics of Parkinson’sdisease.Ann N Y Acad Sci 920:28–32

[4] Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67(2):195–203. https://doi.org/10.1016/j.pharep. 2014.09.004 24.

[5] Elkashef A, Vocci F, Huestis M, Haney M, Budney A, Gruber A, el-Guebaly N (2008) Marijuana neurobiology and treatment. Subst Abus 29(3):17– 29. https://doi.org/10.1080/ 08897070802218166

[6]Augustin SM, Lovinger DM (2018) Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chem Neurosci

[7]Franke TN, Irwin C, Beindorff N, Bouter Y, Bouter C (2019) Effects of tetrahydrocannabinol treatment on brain metabolism and neuron loss in a mouse model of sporadic Alzheimer’sdisease. Nuklearmedizin 58(02):P94. https://doi.org/10.1055/s-00391683689  

[8]Cao C, Li Y, Liu H, Bai G, Mayl J, Lin X, Sutherland K, Nabar N et al (2014) The potential therapeutic effects of THC on Alzheimer’s disease. J Alzheimers Dis 42(3):973–984

[9]Aso E, Andres-Benito P, Carmona M, Maldonado R, Ferrer I (2016) Cannabinoid receptor 2 participates in amyloid-beta processing in a mouse model of Alzheimer’s disease but plays a minor role in the therapeutic properties of a cannabis-based medicine. Journal of Alzheimers Dis : JAD 51(2):489–500. https://doi. org/10.3233/jad-150913