Interplay Between Endocannabinoid System and Neurodegeneration: Focus on Polypharmacology

Abstract

: Pharmacological treatment of complex pathologies such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy.

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model

“…Although both targets and potential hybrids have been evaluated in the context of AD treatment, a synergistic effect has not yet been proven in vivo, which we wanted to address within the context of this work. 38,39 For the design of such hybrids, careful selection of utilized pharmacophores is vital to obtain active hybrid molecules with "balanced" activities. One of the most potent classes of BChE inhibitors (BChEIs) is represented by carbamates, which act in a pseudoirreversible manner, whereas a part of the molecule is transferred onto the ChE.…”

“…However, as AD is a multifactorial disorder, a multitarget medication may deliver the best results for both symptomatic and causal therapy, resulting in a decelerated disease progression and improved cognitive abilities of patients suffering from AD. , To reach these goals, a combination of both a selective h BChE inhibitor and a h CB 2 R agonist was aimed for. Although both targets and potential hybrids have been evaluated in the context of AD treatment, a synergistic effect has not yet been proven in vivo, which we wanted to address within the context of this work. , …”

“…Although both targets and potential hybrids have been evaluated in the context of AD treatment, a synergistic effect has not yet been proven in vivo, which we wanted to address within the context of this work. 38 , 39 …”

Beyond Symptom Management: FAAH Inhibition as a Path to Mitigate Alzheimer’s Disease Progression in Mouse Models of Amyloidosis

“…Among the endogenous systems involved in AD pathophysiology, the pro-homeostatic endocannabinoid system, orchestrating complex lipid signaling pathways within the brain, is increasingly recognized as a pivotal regulator in AD-related neurodegeneration and neuroinflammation (Li et al, 2023;Seghetti et al, 2021). This system includes bioactive lipids such as N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), the type-1 and type-2 cannabinoid receptors (CB 1 and CB 2 ), as well as enzymes and proteins responsible for endocannabinoid synthesis, degradation, and transport (Maccarrone et al, 2023).…”