Endocannabinoids and neurodegenerative diseases

The cannabinoid CB1 and CB2 receptors, the endogenous endocannabinoid (EC) ligands anandamide (AEA) and 2-arachidonylethanolamide, and the degradative enzymes fatty acid amide hydrolase (FAAH) and monoglyceride lipase (ML) are key elements of the EC system implicated in different physiological functions including cognition, motor activity and immune responses. Thus, both the possible neuroprotective role of ECs and their modulating action on neurotransmitter systems affected in several neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD) and multiple sclerosis (NIS) are currently under investigation. Accumulating data show an unbalance in the EC system (i.e. decrease of neuronal cannabinoid CB1 receptors, increase of glial cannabinoid CB2 receptors and over-expression of FAAH in astrocytes) in experimental models of AD as well as in post-mortem brain tissue of AD patients, suggesting its possible role in inflammatory processes and in neuroprotection. However. the mechanisms of the EC modulation of immune response are not fully understood. By contrast, in HD a reduced EC signaling, given both by the loss of cannabinoid CB I receptors and decrease of ECs in brain structures involved in movement control as basal ganglia, has been well documented in preclinical and clinical studies. Thus. in the present review we discuss recent data concerning the role of the EC system in the pathophysiology of AD and HD, two neurode-generative diseases characterized by cognitive deficit and motor impairment, respectively. We focus on the effects of compounds modulating the EC system (agonists/antagonists of cannabinoid CB I and CB2 receptors, or inhibitors of ECs metabolism processes) on the symptoms and/or progression of neurodegenerative diseases. (c) 2007 Published by Elsevier Ltd.