Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

Abstract

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

Role of the endocannabinoid system in neurological disorders

“…Prior to the manifestation of psychiatric symptoms, Δ9‐THC has been shown to induce dopaminergic neuron excitation and increase dopamine levels along the margin of the midbrain region, including the ventral tegmentum, nucleus accumbens, and striatum (Ginovart et al, 2012). Similarly, the reduction in eCB levels as a result of CB2R agonists has also been shown to improve AD symptoms (Paez and Campillo, 2018). Interestingly, increased expression of CB1‐CB2 was observed in microglia in the hippocampus of a transgenic AD mouse model (Navarro et al, 2018).…”

Phytocannabinoids: General Aspects and Pharmacological Potential in Neurodegenerative Diseases

“…Cannabis is an Asian native species from the Family Cannabaceae , being an annual and dioecious plant (and in rare cases can develop as hermaphrodite) [ 16 ]. All species are rich in diverse biologically active chemical constituents divided into 18 chemical classes, including cannabinoids, alkaloids, terpenoids and flavonoids produced by secondary metabolism [ 17 - 19 ]. Based on taxonomy there are three accepted species of Cannabis , known as C. sativa , C. indica and C. ruderalis (Fig.…”

“…Recent studies suggest that THC ( 13, Fig. 3 ) could play an important role in AD, facilitating Aβ disaggregation, reducing tau hyperphosphorilation and even acting as a competitive AChE inhibitor [ 19 ]. In an in vitro PD model using human neuroblastoma SH-SY5Y cells exposed to the toxins MPP + , paraquat and lactacystine, THC showed neuroprotective effects, increasing cell viability and reducing apoptosis and oxidative stress, possibly mediated by PPAR-γ [ 85 ].…”

“…CB2-R is lesser expressed in the CNS than CB1-R, but in some pathological conditions ( e.g . anxiety, epilepsy and AD) its expression can increase, suggesting its involvement in diverse psychiatric illnesses [ 19 , 123 , 126 ]. CB2-R agonist activation causes inactivation of voltage-dependent calcium channels [ 116 ], which leads to a decline in cAMP levels through the MAPK pathway and, in turn, influences cell survival, proliferation and response to stress [ 126 ].…”

Interplay Between Endocannabinoid System and Neurodegeneration: Focus on Polypharmacology

“…The endocannabinoid system (ECS) is involved in the modulation of numerous physiological functions, involving, among others, pain, motor function, immune system, and cognition, and is acquiring an increasingly prominent role as a central nervous system (CNS) regulator of both synaptic transmission and plasticity. Moreover, it may also be responsible for exerting neuroprotective effects following neuronal injury, while, on the other hand, its dysregulation could trigger pathological conditions, including neurological diseases [1,2].…”