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Abstract

THE ROLE OF THE ENDOCANNABINOID SYSTEM IN THE MILD COGNITIVE IMPAIRMENT (MCI), THE PRECURSOR STAGE OF ALZHEIMER’S DISEASE (AD): FACTS AND HYPOTHESES – THE TREATMENT INTERVENTION STRATEGY

Youssef Awni M.D. MPH. and *Prof. Dr. Bowirrat Abdalla M.D., Ph.D.

ABSTRACT

Introduction: Alzheimer‘s disease (AD) is a neurodegenerative disease characterized by functional impairment in the neural elements and circuits underlying cognitive and memory function. The etiology of the disease is multifactorial where genetics and environmental risk factors work in harmony to cause the disease. The condition between normal age-related memory loss and dementia called Mild Cognitive Impairment (MCI). Individuals with MCI have memory problems but are able to perform routine activities such as activity of daily living. MCI often leads to Alzheimer‘s, but not all patients with MCI will develop Alzheimer‘s. Plethoras of therapeutic strategies were implicated to stop the manifestation of the subclinical memory impairment or the development of dementia of Alzheimer‘s type or at least to halt the disease progression. Almost all these efforts were fruitless. We are looking for a new therapeutic strategy to prevent the development of MCI. Novel treatment becomes urgently warranted for improvement the quality of life for patients with this devastating condition and reducing the health care costs attributable to AD, considering the ever-increasing size of this population that expected to triple over the next 50 years. It is well known that depression and stress are considered one of cardinal symptoms of cognitive impairment and accompanied early, the MCI and the prodromal stages of AD. Recently, on the light of the efficacy of Delta9-tetrahydrocannabinol (THC) in the treatmentof stress and depression, these developments draw our attention to the great efficacy of this agent in the treatment of memory impairment. For this, we looked for this new clinically promising neuroprotective molecules that have the property of reducing excitotoxicity and can protect against neuronal damage produced by a variety of neuronal ―insults‖ before the appearance of Mild Cognitive Impairment (MCI) symptomatology, exactly in the initial stage of MCI where depression also represents a surrogate and an indicator sign of memory impairment. The treatment that demonstrate a great efficacy in the treatment of depression (depression triggers the development of cognitive impairment) will be based on the active component of marijuana, Delta9-tetrahydrocannabinol (THC), which competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced Amyloid-β peptide (Aβ) aggregation, the key pathological marker of AD. Computational modeling of the THC-AChE connection discovered that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Our therapeutic intervention strategy is to intervene in this critical stage where Amyloid-β peptide (Aβ) deposition in the brain is strongly suspected to play a key role in Alzheimer‘s because it‘s the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer‘s — may, in the disease‘s earliest stages, impair learning and memory by blocking the natural, beneficial action of a neuroprotective agents such as (endocannabinoids, in the brain. It was demonstrated that natural substances such as Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. Studying this the properties of this agents prompted us to study the localization, expression and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after Aβ treatment, both in vivo and in vitro. Here we review the mechanisms for the regulation of their levels under physiological and pathological conditions, and recent findings on their role in disease. Here, we review the contribution of degenerative and inflammatory processes to CNS we also discuss the apparently unique opportunity to modify neurodegeneration and neuroinflammation simultaneously by pharmacological manipulation of the endocannabinoid system in the CNS and in peripheral immune cells. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverseeffects and increase the efficacy of cannabinoid treatment. Conclusion: Cannabinoids have been proposed as clinically promising neuroprotective molecules, based on their capability to normalize glutamate homeostasis, reducing excitotoxicity, to inhibit calcium influx, lowering intracellular levels and the subsequent activation of calcium-dependent destructive pathways, and to reduce the generation of reactive oxygen intermediates or to limit their toxicity, decreasing oxidative injury. Cannabinoids are also able to decrease local inflammatory events by acting on glial processes that regulate neuronal survival and to restore blood supply by reducing vasocontriction produced by several endothelium-derived factors. Areas covered in this review: Current literature supporting these neuroprotective effects, particularly evidence generated during the last ten years, concentrating on targets within the cannabinoid signaling system that facilitate these effects. Acute or chronic neurodegenerative disorders where cannabinoids have shown neuroprotective effect. Increased research on cannabinoid medicine and modulation of the endocannabinoid system in relation to AD and other neurodegenerative diseases has the potential to not only lead to symptom management for patients, but also potentially to novel therapies which may help to prevent progression and potentially initiation, of the disease. In this review we recommend the following suggestions: 1. Active component of marijuana, Delta9-tetrahydrocannabinol (THC), will be used in the early stage of MCI. 2. Simple size will be initially more than 250 individuals suffering from mild cognitive impairment and who also have a depressive symptoms. 3. MCI patients will be diagnosed according to DSM-IV criteria and by using screening test as MMSE. 4. Close follow up and evaluations of cognitive status will be periodically performed (every three months).

Keywords: neurodegeneration and neuroinflammation simultaneously.


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