The Endocannabinoid System in Ageing: A New Target for Drug Development

Abstract

Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. AEA is released "on demand" from membrane lipids, and its activity at the receptors is limited by cellular uptake followed by intracellular hydrolysis. Together with AEA and congeners, the proteins which bind, synthesize, transport and hydrolyze AEA form the "endocannabinoid system". Endogenous cannabinoids are present in the central nervous system and in peripheral tissues, suggesting a physiological role as broad spectrum modulators. This review summarizes the main features of the endocannabinoid system, and the latest advances on its involvement in ageing of central and peripheral cells. In addition, the therapeutic potential of recently developed drugs able to modulate the endocannabinoid tone for the treatment of ageing and age-related human pathologies will be reviewed.

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

“…Whereas the PE pressor method measures BRS after evoked changes in AP in an open-loop system, the spontaneous method measures changes in a closed-loop model over a much smaller (beat-to-beat) range, although a highly significant correlation exists between them (16). Collectively, blockade of endocannabinoid actions at NTS CB 1 receptors improved blood pressure regulation in older SD rats as assessed using several indices of BRS and sympathovagal function, consistent with upregulated systemic CB 1 receptor tone during conditions associated with aging including hypertension (6) and metabolic syndrome (5). …”

“…Alterations in the brain endocannabinoid system that accompany age-related cognitive decline (4), cardiovascular diseases or metabolic disorders (5) may contribute to the modulation of baroreflex function during aging. The endocannabinoid system is a central and peripheral cellular signaling system that comprises the endogenous cannabinoids anandamide and 2-arachidonoylglycerol (2-AG), their G protein-coupled CB 1 and CB 2 receptor subtypes, and enzymes regulating their biosynthesis and degradation.…”

Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

“…Additionally, the ECS is known to play a key role in pathological events occurring in the AD brain: excitotoxicity [12], oxidative stress [13] and inflammation [2]. Yet, few studies investigated alterations of the ECS in normal or pathological aging (reviewed in Paradisi et al [14]). For example, it has been reported that CB 1 receptors are decreased in aged rats [15], [16] and in human pathological conditions affecting basal ganglia structures [17], and CB 1 receptor in human AD brains mainly demonstrates no changes [18], [19], [20] or decreased levels [21], [22].…”

Cannabinoids enhance gastric X/A-like cells activity.

“…Marijuana is a well-known recreational drug that has for centuries been prescribed therapeutically in herbal medicine for the treatment of many disorders, including loss of appetite [1]. The identification of the major active constituent of marijuana, Δ 9 -THC [2], followed by the biochemical and pharmacological characterization of the cannabinoid receptors [3,4], provided a solid foundation and opened a new perspectives for the study of this neurochemical system [5].…”