Selective Modulator of Cannabinoid Receptor Type 2 Reduces Memory Impairment and Infarct Size During Cerebral Hypoperfusion and Vascular Dementia

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.

Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

“…Previous studies in primary rat cell cultures have reported that activation of CB 2 R can obviously inhibit the LPS-induced transition of microglia to the Ml phenotype and thereby prevent M1-mediated inflammatory responses [ 37 ]. Further, in an animal model of VD, the selective activation of CB 2 R improves memory deficit and infarct size in chronic brain hypoperfusion [ 38 ]. In support of these reports, our findings demonstrated that in the VD model rats which received either PF or a specific pharmacological CB 2 R agonist HU308, hippocampal CB 2 R mRNA and protein expression levels in 4-VO rats at the recovery stage of ischemia were further increased compared with that in the untreated 4-VO group.…”

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective

“…The administration of TWK10-fermented soymilk extract also increases the scavenging activity of α,α-diphenyl-βpicrylhydrazyl (DPPH) and the activity levels of CAT, GSH, and SOD [33]. Additionally, 1-phenylisatin, a selective cannabinoid receptor type 2 (CB2R) agonist, has the same effects as those of TWK10-fermented soymilk extract in CCH-induced VaD rats [34]. Edaravone is a novel free radical scavenger that ameliorates neuronal damage and exerts neuroprotective effects in neurodegenerative diseases [35,36].…”

The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling?

“…Collectively, these studies provide emerging evidence supporting an important role for the ECS – NO • signalling axis in controlling the physiological actions and/or viability of key cellular components of the CNS (i.e. neurons, astrocytes, microglia, brain microvascular endothelial cells), thereby impacting on cognitive and neuroendocrine function, as well as implicating the ECS – NO • pathway as a potential therapeutic target to alleviate neurodegeneration in response to brain injury and neurological conditions such as Parkinson's disease, vascular dementia, and Alzheimer's disease (Koppel et al, 2014; Aso et al, 2016; Austin and Katusic, 2016; Gomez-Galvez et al, 2016; Jayant and Sharma, 2016). …”