Neurotherapeutic potential of Delta-9- Tetrahydrocannabinol on D-galactose and aluminium chloride induced Alzheimer-like animal model

Cognitive impairment and neurodegeneration have been well documented as a disorder of old age diseases including Alzheimer’s disease (AD). D-galactose (D-gal) has been identified as senescence agent, whereas aluminium chloride (AlCl3) is a neurotoxin implicated in the pathogenesis of AD. The cannabinoid agonist delta-9- tetrahydrocannabinol (∆9 THC) has evolved as a therapeutic compound for neurodegenerative diseases. The present study has been designed to explore the neurotherapeutic potential of ∆9 THC on cognition, brain histology and neurogenesis activity in Wistar rats induced by D-gal and AlCl3. The expression of AD pathological hallmarks was also been evaluated. Male albino Wistar rats were injected intraperitoneally with 60 mg/kg D-gal and orally with 200 mg/kg AlCl3, once daily for 10 consecutive weeks. After 10 weeks, ∆9 THC at 0.75, 1.5 and 3.0 mg/kg and 1 mg/kg donepezil were administered intraperitoneally for 28 days as a part of treatment phase. Behavioural assessments such as novel object recognition (NOR), Morris water maze (MWM), elevated plus maze (EPM) and modified elevated plus maze (mEPM) were evaluated, along with histological examination of the hippocampus. Additionally, neurogenesis markers (GFAP, DCX, NeUN and Calbindin) and AD pathological hallmark markers (BACE 1, APP, p-tau Thr181 and p-tau Thr231) were evaluated in the hippocampus. The results revealed that rats treated with 60 mg/kg D-gal + 200 mg/kg AlCl3 exhibited cognitive impairment in both spatial and non-spatial learning and memory test, associated with neurodegeneration as evidenced by a decrease in the number of survival pyramidal cells and granule cells (p<0.05), as well as fluctuation in the thickness layer of the hippocampus (p<0.05). It also caused marked decreased in all neurogenesis markers (p<0.05). The expression of BACE1, APP, p-tau Thr181 and p-tau Thr231 were also increased significantly (p<0.05). Treatment with ∆9 THC, with irrespective of doses, alleviated the D-gal + AlCl3 induced AD-like pathology in rats. These include improved spatial learning and memory as measured by behavioural tests (p<0.05), ameliorates from pyramidal and granule cell loss (p<0.05) and increased thickness layer of the hippocampus (p<0.05). Further, ∆9 THC enhances neurogenesis activity by marked increase of all neurogenesis markers. The expression of AD-related pathological hallmarks was also suppressed by ∆9 THC. These findings provide scientific evidence and open the opportunity to use cannabinoid agonist (∆9 THC) as a potential treatment against AD.

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