Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage (original) (raw)
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The dual neuroprotective-neurotoxic profile of cannabinoid drugs
British Journal of Pharmacology, 2011
Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/ neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of D 9-tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre-or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.
Behavioural Brain Research, 2010
A single administration of an extremely low dose (0.002 mg/kg) of 9-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to ICR mice induced long-term cognitive deficits that lasted for at least 5 months. The behavioral deficits were detected by several tests that evaluated different aspects of memory and learning, including spatial navigation and spatial and non-spatial recognition. Our findings point to possible deficits in attention or motivation that represent a common upstream cognitive process that may affect the performance of the mice in the different behavioral assays. Similar ultra-low doses of THC (3-4 orders of magnitude lower than doses that are known to evoke the acute effects of THC) also induced sustained activation of extracellular-regulated kinase (ERK1/2) in the cerebellum, indicating that a single injection of such low doses of the cannabinoid drug can stimulate neuronal regulatory mechanisms. The relevance of these findings to the behavioral consequences of chronic exposure to marijuana is discussed.
A single low dose of tetrahydrocannabinol induces long-term cognitive deficits
Neuroscience Letters, 2007
9-Tetrahydrocannabinol (THC) was shown to exert either neuroprotective or neurotoxic effects. Based on our in vitro studies and on pharmacokinetic considerations, we have recently presented a hypothesis that explains this dual activity of THC. This explanation is based on the assumption that extremely low doses of cannabinoids are neurotoxic. The present study verifies this assumption and shows that a single injection of 0.001 mg/kg THC (3-4 orders of magnitude lower than conventional doses) significantly affected the performance of mice in the Morris water maze test 3 weeks later. The THC-injected mice showed both longer escape latencies and lower scores in the probe tests compared to their matched controls, indicating the induction of cognitive deficits.
Neuropharmacology, 2007
Both Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol are known to have a neuroprotective effect against cerebral ischemia. We examined whether repeated treatment with both drugs led to tolerance of their neuroprotective effects in mice subjected to 4h-middle cerebral artery (MCA) occlusion. The neuroprotective effect of Delta(9)-THC but not cannabidiol was inhibited by SR141716, cannabinoid CB(1) receptor antagonist. Fourteen-day repeated treatment with Delta(9)-THC, but not cannabidiol, led to tolerance of the neuroprotective and hypothermic effects. In addition, repeated treatment with Delta(9)-THC reversed the increase in cerebral blood flow (CBF), while cannabidiol did not reverse that effect. Repeated treatment with Delta(9)-THC caused CB(1) receptor desensitization and down-regulation in MCA occluded mice. On the contrary, cannabidiol did not influence these effects. Moreover, the neuroprotective effect and an increase in CBF induced by repeated treatment with can...
Δ9-Tetrahydrocannabinol protects hippocampal neurons from excitotoxicity
2007
Excitotoxic neuronal death underlies many neurodegenerative disorders. Because cannabinoid receptor agonists act presynaptically to inhibit glutamate release, we examined the effects of Win 55212-2, a full agonist at CB 1 receptors, and Δ 9-tetrahydrocannabinol (THC), a partial agonist, on the survival of neurons exposed to an excitotoxic pattern of synaptic activity. Reducing the extracellular Mg 2+ concentration ([Mg 2+ ] o) to 0.1 mM evoked an aberrant pattern of glutamatergic activity that produced synaptically mediated death of rat hippocampal neurons in culture. Neuronal viability was quantified with a multiwell fluorescence plate scanner equipped to detect propidium iodide fluorescence. Win 55212-2 (100 nM) and THC (100 nM) significantly reduced 0.1 mM [Mg 2+ ] o-induced cell death by 77 ± 11% and 84 ± 8%, respectively. Interestingly, the protection afforded by THC was not significantly different from that produced by Win 55212-2, suggesting that attenuation without a complete block of excitatory activity is sufficient for neuroprotection. The effect of prolonged drug exposure on the neuroprotection afforded by cannabinoid receptor agonists was also studied. When cultures were pretreated for 24 h with Win 55212-2 (100 nM) or THC (100 nM), inhibition of 0.1 mM [Mg 2+ ] o-induced toxicity was significantly reduced to 39 ± 19% and 45 ± 13%, respectively. Thus, desensitization of CB 1 receptors diminishes the neuroprotective effects of cannabinoids. This study demonstrates the importance of agonist efficacy and the duration of treatment on the neuroprotective effects of cannabinoids. It will be important to consider these effects on neuronal survival when evaluating pharmacologic treatments that modulate the endocannabinoid system.
A single in-vivo exposure to Δ9THC blocks endocannabinoid-mediated synaptic plasticity
Nature Neuroscience, 2004
Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to ∆9tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.
STUDY: MEDICAL MARIJUANA CAN MINIMIZE BRAIN DAMAGE
A new study has revealed that medical marijuana includes qualities that could protect the brain from long-term damage after a traumatic injury. The protective effects come from the cannabinoid THC (or tetrahydrocannabinol), the major psychoactive component in the cannabis plant. This latest study implies that medical marijuana might one day help reduce the risk of brain damage after critical surgery.
Biphasic effects of THC in memory and cognition
European Journal of Clinical Investigation, 2018
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.
Cannabis Therapeutics and the Future of Neurology
Frontiers in Integrative Neuroscience
Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabisbased medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB 1 and CB 2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptorgamma (PPARγ; THCA), 5-HT 1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.