Salubrious effects of ulinastatin and quercetin alone or in combination in endothelial dysfunction and vascular dementia.

BACKGROUND: Vascular dementia is the second most prevalent form of dementia. Hypertension is the leading risk factor for endothelial dysfunction and the progression of dementia that is of vascular origin. This study investigates the role of ulinastatin (UTI) and quercetin alone as well as in combination in hypertension-induced endothelial dysfunction and vascular dementia (VaD). METHOD: Two-kidney one-clip (2K1C) renovascular model was set up to induce hypertension in the Albino Wistar rats (males). Rats were assessed for mean arterial blood pressure, behavioral function (Morris water maze, attention set-shifting tests), vascular endothelial function, and biochemical levels (aortic superoxide anion and serum nitrite/nitrate), as well as brains' thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, interleukin-6, 10, tumor necrosis factor-TNF-α and acetylcholinesterase-AChE). UTI (10,000 U/kg, ip) and quercetin (60 mg/kg) were used alone and in combination for treatment. Donepezil (0.5 mg/kg) was used as a positive control. RESULTS: 2K1C rats showed impairment in learning, memory, executive functioning, and reversal learning. These rats further showed endothelial dysfunction as well as an increase in mean arterial blood pressure, brains' oxidative stress, inflammation, and AChE-activity. Treatment with UTI and quercetin alone as well in combination significantly attenuated the 2K1C model induced impairments in the behavioural, biochemical, and endothelial parameters. CONCLUSION: 2K1C renovascular hypertension-induced impairment in behavioural, biochemical, and endothelial parameters were attenuated by the treatment with UTI and quercetin alone as well as in combination. Therefore, the utility of these agents might be studied further to understand their full potential in hypertension-induced VaD.

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

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.

Selective modulator of cannabinoid receptor type 2 (CB2) against biochemical alterations and brain damage in chronic cerebral hypoperfusion induced vascular dementia.

Vascular dementia is the second most common cause of cognitive decline in aged people but the effectual therapeutic target is still missing. Chronic cerebral hypoperfusion (CCH) has been widely found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive impairment. The present study has been framed to investigate the role of selective agonist of CB2 receptor (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 complex activity (complexes I, II, IV) with the enhancement in cholinergic activity- AChE and brain infarct size (TTC staining). These animals have also shown a considerable increase in brain edema (water content). Oral administration of 1-phenylisatin has significantly recuperated 2VO induced impairment in learning-memory, increase in TBARS, GSH, CAT, SOD, mitochondrial activity with a significant reduction in AChE activity and brain damage. Administration of 1-phenylisatin has also been reported to recover 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 in cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD. Therefore, pharmacological positive modulation of CB2 receptors may be a potential research target for alleviation of VaD.

Protective effect of transient receptor potential vanilloid subtype 1 (TRPV1) modulator, against behavioral, biochemical and structural damage in experimental models of Alzheimer's disease.

Alzheime's disease (AD) is an overwhelming neurodegenerative disorder, characterized by synaptic dysfunction, memory loss, neuro-inflammation and neural cell death. Very few treatments are in hand for the management of AD and they are only concentrating on peculiar aspects. Hence, an immense thrust is required to find utmost therapeutic targets to conquer this condition. This study investigates a potential role of vanillin, a selective agonist of transient receptor potential vanilloid subtype 1 (TRPV1) in the experimental models of AD viz. intracerebroventricular (i.c.v.) streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose induced AD in mice. The i.c.v. administration of STZ and intraperitoneally administration of AlCl3+d-galactose have significantly impaired learning-memory (Morris water maze and attentional set-shifting test), brain structure (hematoxylin, eosin and Congo red staining), enhanced brain oxidative stress (thiobarbituric acid reactive substance - TBARS and glutathione - GSH), nitrosative stress (nitrite/nitrate), acetylcholinesterase activity (AChE), inflammation (MPO), and calcium levels (Ca(++)). Treatment with vanillin in different doses and donepezil have significantly ameliorated i.c.v. STZ and AlCl3+d-galactose induced reduction in executive function, impaired reversal learning, cognition, memory and brain damage. Treatment with these drugs has also reduced the brain oxidative stress (TBARS and GSH), nitrosative stress (nitrite/nitrate), and AChE, MPO, and Ca(++) levels. These results indicate that vanillin, a selective agonist of TRPV1 and donepezil, a potent acetylcholine esterase inhibitor have attenuated i.c.v. STZ and AlCl3+d-galactose induced experimental AD. Hence, pharmacological positive modulation of TRPV1 channels may be a potential research target for mitigation of AD.

Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world. Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition. The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition. We have induced experimental AD in mice by using two induction models viz., intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose. Morris water maze (MWM) and attentional set shifting test (ASST) were used to assess learning and memory. Hematoxylin-eosin and Congo red staining were used to examine the structural variation in brain. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), nitric oxide levels (nitrites/nitrates), acetyl cholinesterase activity, myeloperoxidase and calcium levels were also estimated. i.c.v. STZ as well as AlCl3+d-galactose have impaired spatial and reversal learning with executive functioning, increased brain oxidative and nitrosative stress, cholinergic activity, inflammation and calcium levels. Furthermore, these agents have also enhanced the burden of Aß plaque in the brain. Treatment with 1-phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of learning-memory, brain biochemistry and brain damage. Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD.