Biphasic effects of THC in memory and cognition
Edward J. Calabrese, Alberto Rubio-Casillas
European Journal of Clinical Investigation, 2018, 48, e12920.
A generally undesired effect of cannabis smoking is a reversible disruption of short-term memory induced by delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. However, this paradigm has been recently challenged by a group of scientists who have shown that THC is also able to improve neurological function in old animals when chronically administered at low concentrations. Moreover, recent studies demonstrated that THC paradoxically promotes hippocampal neurogenesis, prevents neurodegenerative processes occurring in animal models of Alzheimer’s disease, protects from inflammationinduced cognitive damage and restores memory and cognitive function in old mice. With the aim to reconcile these seemingly contradictory facts, this work will show that such paradox can be explained within the framework of hormesis, defined as a biphasic dose-response.
Keywords : Alzheimer’s disease, biphasic dose response, cannabis, delta-9-tetrahydrocannabinol, hormesis, neuroprotection
1 | INTRODUCTION
Alzheimer’s disease (AD) is characterized by progressive deterioration of cognitive functions and oxidative stress,1 with biochemical alterations consisting in the accumulation of amyloid-b (Ab) protein in the form of senile plaques2 and intracellular neurofibrillary tangles (associated with hyperphosphorylated tau protein and neuronal cell depletion). 3-6 Although familial and sporadic AD differs in their cause, the progression of the disease from this point onwards appears to be the same. These alterations induce neuroinflammation and oxidative stress, which creates a neurotoxic environment that potentiates neurodegeneration and eventually leads to cognitive decline.7,8 Also, Abinduced neurodegeneration elevates glutamate levels in the cerebral spinal fluid of patients with AD,9 and cholinergic neurons are lost in brain areas relevant for memory processing (and accompanied by a decrease in acetylcholine). 10 In normal conditions, memory, learning and behaviour depend on the proper function of the excitatory glutamate N-methyl-D-aspartate-receptor (NMDAR) and a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and underlying mechanisms of synaptic plasticity. 11-13 However, the dysregulation of intracellular Ca2+ homoeostasis14 and excessive activation of the N-methyl D-aspartate (NMDA) subtype of the glutamate receptor, leading to excitotoxicity, are features of the AD brain.15 All of the clinical mutations in the presenilin genes (PS1/ PS2) that have been linked with the inherited form of AD disrupt calcium signalling,14 which may contribute to subsequent neurodegeneration and memory impairments.