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Selective Modulator of Cannabinoid Receptor Type 2 Reduces Memory Impairment and Infarct Size During Cerebral
Shalini Jayant, Bhupesh Sharma1
1Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, A-Block, Ground Floor, Sector-125, Noida - 201303, Uttar Pradesh, India; And CNS and CVS Pharmacology, Conscience Research, Pocket F-233, B, Dilshad Garden, Delhi-110095 India. drbhupeshresearch@gmail.com.
Insights
1-phenylisatin, a selective CB2 receptor agonist, improved cognitive deficits and reduced brain damage in rats with chronic cerebral hypoperfusion (CCH). This suggests CB2 receptor modulation may be a therapeutic target for vascular dementia (VaD).
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Vascular dementia (VaD) is a significant neurodegenerative disorder linked to chronic cerebral hypoperfusion (CCH).
- Effective therapeutic targets for VaD remain elusive.
- CCH is associated with cognitive decline and neurodegeneration.
Purpose of the Study:
- To investigate the therapeutic potential of 1-phenylisatin, a selective cannabinoid receptor type 2 (CB2) agonist, in a rat model of CCH-induced VaD.
- To assess the effects of 1-phenylisatin on cognitive function, oxidative stress, mitochondrial activity, and brain edema.
Main Methods:
- Chronic cerebral hypoperfusion (CCH) was induced in rats using the two-vessel occlusion (2VO) technique.
- Cognitive function was evaluated using the Morris water maze and Attentional set-shifting test.
- Biochemical markers of oxidative stress (TBARS, GSH, CAT, SOD), mitochondrial function, cholinergic activity (AChE), and brain infarct size were assessed.
Main Results:
- 2VO-induced CCH rats exhibited significant learning-memory and executive function impairments.
- CCH led to increased oxidative stress, mitochondrial dysfunction, elevated AChE activity, and brain edema.
- 1-phenylisatin treatment significantly ameliorated cognitive deficits, reduced oxidative stress and brain edema, and improved mitochondrial activity.
Conclusions:
- The 2VO model effectively replicates CCH-induced VaD characteristics in rats.
- 1-phenylisatin demonstrates neuroprotective effects by mitigating CCH-induced brain damage and cognitive impairment.
- Modulation of CB2 receptors represents a promising therapeutic strategy for CCH and VaD.
Abstract:
Vascular dementia is the highly devastating neurodegenerative disorder after Alzheimer's disease (AD) and mainly found in aged people but the effectual therapeutic target is still not there. Chronic cerebral hypoperfusion (CCH) has been broadly found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive deteriorate on. This study has been framed to examine the role of a selective agonist of cannabinoid receptor type 2(CB2); 1-phenylisatin in CCH induced VaD. Permanent bilateral common carotid arteries ligation or two vessels occlusion (2VO) technique was used to induce CCH in rats. 2VO animals have shown significant impairment in learning-memory (Morris water maze) and in executive functioning (Attentional set-shifting test). These animals have shown a considerable reduction in brain oxidative stress (thiobarbituric reactive acid substance-TBARS; glutathione-GSH; catalase-CAT and superoxide dismutase-SOD), mitochondrial dysfunction (complexes I, II, IV) with a significant enhancement in cholinergic activity- AChE and brain infarct size2,3,5-triphenylterazolium chloride staining (TTC staining). Animals treated with 2VO have also demonstrated a considerable augmentation in brain edema (water content). Oral administration of 1-phenylisatin has significantly recuperated 2VO induced impairment in learning-memory, an increase in TBARS, GSH, CAT, SOD, mitochondrial activity with a significant reduction in AChE activity and brain damage. Administration of 1- phenylisatin has also reported recovering brain edema in these animals. These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin. Hence, it may be suggested that modulation of cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD. Therefore, selective agonists of CB2 receptors may be a potential research target for the alleviation of VaD.
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