Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels along with increase in serum & brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia.     

Pharmacological investigation of memory restorative effect of riluzole in mice

Objective:

Streptozotocin (STZ) and sodium nitrite (NaNO₂) treatment have been positively correlated with higher incidence of memory loss and experimental dementia. The present study was designed to investigate the potential of the Riluzole, an inhibitor of glutamatergic neurotransmission and activator of TWIK-Related K⁺ channels with incidences of memory deficits associated with dementia in mice.

Materials and Methods:

Dementia was induced in Swiss albino mice by intracerebroventricular STZ (ICV) and by subcutaneous NaNO₂ in separate groups of animals. Morris water maze was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed so as to assess brain acetyl cholinesterase (AChE) activity. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured to assess total oxidative stress.

Results:

Treatment of ICV STZ and NaNO₂ produced a significant decrease in water maze performance of mice hence reflecting loss of learning and memory. Furthermore, higher levels of brain AChE activity and oxidative stress were observed in these animals. Administration of riluzole (5 and 10 mg/kg intraperitoneally) successfully attenuated memory deficits as well as ICV STZ- and NaNO₂ -induced changes in the levels of brain AChE, TBARS, and GSH.

Conclusion:

The memory restorative effects of riluzole in dementia may involve its multiple functions including anti-oxidative and anticholinesterase properties.KEY WORDS: Riluzole, streptozotocin, dementia, TREK, morris water-maze     

Modulation of celecoxib- and streptozotocin-induced experimental dementia of Alzheimer's disease by pitavastatin and donepezil

Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.     

Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.     

Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

The present study was undertaken to explore the potential of erythropoietin in memory deficits of mice. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) and intracerebroventricular streptozotocin (i.c.v STZ, 3 mg/kg, 10 µl, 1^st and 3^rd day) in separate groups of animals. Morris water-maze test was employed to assess learning and memory. The levels of brain thio-barbituric acid reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess degree of oxidative stress. Brain acetylcholinesterase enzyme (AChE) activity was also measured. Scopolamine/streptozotocin administration induced significant impairment of learning and memory in mice as indicated by marked decrease in Morris water-maze performance. Scopolamine/streptozotocin administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (an increase in TBARS and a decrease in GSH) levels. Treatment of erythropoietin (500 and 1,000 IU/Kg i.p.) significantly reversed scopolamine- as well as streptozotocin-induced learning and memory deficits along with attenuation of those-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that erythropoietin exerts a beneficial effect in memory deficits of mice possibly through its multiple actions including potential anti-oxidative effect.     

Behavioral and biochemical investigations to explore pharmacological potential of PPAR-gamma agonists in vascular dementia of diabetic rats

Vascular dementia (VaD) is the second most common dementing illness. We have recently reported that diabetes induces VaD in rats. The present study has been designed to investigate the potential of peroxisome-proliferator-activated receptors-gamma (PPAR-γ) agonists in diabetes induced VaD of Wistar Albino rats. The rats were administered, single dose of streptozotocin (STZ) for the induction of diabetes. Morris water-maze (MWM) test was employed for testing learning and memory. Serum glucose, bodyweight, vascular endothelial function, serum nitrite/nitrate levels, aortic and brain oxidative stress levels (viz. aortic superoxide anion levels, brain thiobarbituric acid reactive species and brain glutathione levels) and brain acetylcholinesterase activity were also tested. STZ treated animals performed poorly on MWM hence reflecting impairment of learning and memory behavior with a significant reduction in body weight, impairment of vascular endothelial function, and decrease in serum nitrite/nitrate levels, increase in serum glucose, aortic and brain oxidative stress levels and brain acetylcholinesterase activity. Treatment of PPAR-γ agonists, pioglitazone as well as rosiglitazone significantly reversed, diabetes induced impairment of learning and memory behavior, endothelial function, and changes in various biochemical parameters. It is concluded that PPAR-γ modulators pioglitazone and rosiglitazone may be considered as potential pharmacological agents for the management of diabetes induced VaD.     

Antiamnesic effect of stevioside in scopolamine-treated rats

The present study was undertaken to explore the potential of stevioside in memory dysfunction of rats. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) in animals. Morris water maze (MWM) test was employed to assess learning and memory. Brain acetylcholinestrase enzyme (AChE) activity was measured to assess the central cholinergic activity. The levels of brain thiobarbituric acid-reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess the degree of oxidative stress. Scopolamine administration induced significant impairment of learning and memory in rats, as indicated by a marked decrease in MWM performance. Scopolamine administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (increase in TBARS and decrease in GSH) levels. Pretreatment of stevioside (250 mg/kg dose orally) significantly reversed scopolamine-induced learning and memory deficits along with attenuation of scopolamine-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that stevioside exerts a memory-preservative effect in cognitive deficits of rats possibly through its multiple actions.     

Memory restorative role of statins in experimental dementia: an evidence of their cholesterol dependent and independent actions

The study was aimed at investigating the effects of pitavastatin, simvastatin (lipophilic statins) and fluvastatin (hydrophilic statin) on memory deficits associated with Alzheimer's type dementia in mice. Dementia was induced with chronic administration of a high fat diet (HFD) or intracebroventricular streptozotocin (icv STZ, two doses of 3 mg/kg) in separate groups of animals. Memory of the animals was assessed by the Morris water maze (MWM) test. Brain thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) levels were measured to assess total oxidative stress. Brain acetylcholinesterase (AChE) activity and total serum cholesterol levels were also measured. Icv STZ or HFD produced a significant impairment of learning and memory. Higher levels of brain AChE activity and TBARS and lower levels of GSH were observed in icv STZ- as well as HFD-treated animals. HFD-treated mice also showed a significant increase in total serum cholesterol levels. Pitavastatin and simvastatin each significantly attenuated STZ-induced memory deficits and biochemical changes; however, fluvastatin produced no significant effect on icv STZ-induced dementia or biochemical levels. Administration of any one of the three statins not only lowered HFD-induced rise in total serum cholesterol level but also attenuated HFD-induced memory deficits. Further pitavastatin and simvastatin administration also reversed HFD-induced changes in biochemicals level, while fluvastatin failed to produce any significant effect. This study demonstrates the potential of statins in memory dysfunctions associated with experimental dementia and provides evidence of their cholesterol-dependent and -independent actions.     

Defensive effect of natrium diethyldithiocarbamate trihydrate (NDDCT) and lisinopril in DOCA–salt hypertension-induced vascular dementia in rats

Rationale

Vascular dementia and hypertension are increasing day by day, with a high degree of co-occurrence. Tremendous amount of research work is required so that new pharmacological agents may be identified for their appropriate therapeutic utility to combat different dementing disorders.

Objectives

This study investigates the effect of natrium diethyldithiocarbamate trihydrate (NDDCT), a nuclear factor kappa-B (NF-??B) inhibitor, as well as lisinopril, an angiotensin converting enzyme (ACE) inhibitor, on deoxycorticosterone acetate (DOCA) hypertension-induced vascular dementia in rats.

Methods

DOCA was used to induce hypertension and associated vascular dementia. Morris water maze (MWM) was used for testing learning and memory. Endothelial function was assessed by acetylcholine-induced endothelium-dependent relaxation of aortic strips. Different biochemical estimations were used to assess oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, and brain glutathione), nitric oxide levels (serum nitrite/nitrate), and cholinergic activity (brain acetyl cholinesterase activity).

Results

DOCA treatment significantly raised the mean arterial blood pressure of rats, and these hypertensive rats performed poorly on MWM, reflecting impairment of learning and memory. DOCA treatment also impaired vascular endothelial function and different biochemical parameters. Treatments of NDDCT as well as lisinopril significantly attenuated DOCA hypertension-induced impairment of learning and memory, endothelial dysfunction, and changes in various biochemical levels.

Conclusions

DOCA?Csalt hypertension induces vascular dementia in rats. NF-??B as well as ACE inhibitors may be considered as potential pharmacological agents for the management of hypertension-induced vascular dementia.     

Exploitation of HIV protease inhibitor Indinavir as a memory restorative agent in experimental dementia

The present study was undertaken to investigate the beneficial effect of HIV protease inhibitor Indinavir on memory deficits associated with experimental dementia of Alzheimer disease's (AD) type. Dementia was induced in Swiss albino mice by administration of Celecoxib (100 mg kg^− 1 orally, daily for 9 days) or Streptozotocin (3 mg kg^− 1 administered intracerebroventricularly on 1st and 3rd day) and the cognitive behaviors of Swiss albino mice were assessed using Morris water maze test. Brain acetyl cholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Donepezil (0.1 mg kg^− 1 i.p.) served as positive control in the present investigation. Celecoxib as well as Streptozotocin (STZ) produced a significant loss of learning and memory. Indinavir (100 and 200 mg kg^− 1 orally) successfully attenuated Celecoxib as well as STZ induced cognitive deficits. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in Celecoxib as well as STZ treated animals, which were significantly attenuated by Donepezil and Indinavir. Study highlights the potential of Indinavir in memory dysfunctions associated with dementia of AD.     

No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers

Ambrisentan is a nonsulfonamide, ET_A-selective endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), and tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor under investigation for treatment of PAH. Due to the potential combination use, the pharmacokinetic (PK) interactions between these two drugs were assessed in a crossover study in 26 healthy adults. Single-dose PK of ambrisentan (10 mg) and its metabolite, 4-hydroxymethyl ambrisentan, were determined in the absence and presence of multiple doses of tadalafil (40 mg QD). Similarly, single-dose PK of tadalafil (40 mg) were evaluated in the absence and presence of multiple doses of ambrisentan (10 mg QD). In the presence of tadalafil, ambrisentan maximum plasma concentration (C_max) was similar (105.0% [90% CI: 95.9–115.0%]) and systemic exposure (AUC_0–∞) was slightly decreased (87.5% [84.0–91.2%]), compared with ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan. Tadalafil C_max (100.6% [94.4–107.1%]) and AUC_0–∞ (100.2% [92.6–108.4%]) showed no difference in the absence and presence of ambrisentan. The safety profile of the drugs combined was similar to that of either drug alone. No dose adjustments should be necessary when these drugs are coadministered. These results are in contrast to previous reports that the sulfonamide-based ERA bosentan can cause marked decreases in the exposure of tadalafil. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4962–4974, 2009     

Involvement of PPAR-gamma in curcumin-mediated beneficial effects in experimental dementia

The present study was undertaken to investigate the possible mechanism of curcumin-mediated beneficial effects in memory deficits associated with experimental dementia. Dementia was induced in Swiss albino mice by administrating streptozotocin (3 mg kg⁻¹) intracerebroventricularly on first and third day. Morris water maze test was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed to assess brain acetyl cholinesterase (AChE) activity and total oxidative stress. Streptozotocin (STZ) produced a significant decrease in water maze performance of mice indicative of impairment in spatial reference memory. Curcumin (20 mg/kg p.o. daily for 14 days) successfully attenuated STZ-induced memory deficits. Higher levels of brain AChE activity and oxidative stress were observed in STZ-treated animals, which were significantly attenuated by curcumin. Furthermore, the noted beneficial effect of curcumin on STZ-induced dementia was significantly abolished by pretreatment with PPAR-γ receptor antagonist bisphenol-A-diglycidyl ether, i.e., BADGE (30 mg/kg intraperitoneally (i.p.)). It may be concluded that the beneficial effects of curcumin are mediated through the activation of PPAR-γ receptors.     

Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension

The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension (PAH). Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis, cell proliferation, and inflammation caused by endothelin. Prior to October 2013, ambrisentan, a selective ET_A receptor antagonist and bosentan, a dual ET_A/ET_B antagonist, were the only currently available agents for PAH targeting the endothelin pathway. Based on the results of the SERAPHIN trial, macitentan (brand name Opsumit^®), a new ET_A/ET_B antagonist, has been US FDA approved to delay disease progression and reduce hospitalizations for PAH. SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality. Previous trials have focused on short-term outcomes, such as improved 6-min walk distance and WHO functional class.     

Memory restorative ability of clioquinol in copper–cholesterol-induced experimental dementia in mice

Abstract

Context: Results from various studies indicate that the presence of certain heavy metals such as aluminum (Al), arsenic (As), copper (Cu), lead (Pb), and mercury (Hg) may enhance the aggregation of Aβ and oxidative stress levels leading to neuronal toxicity and Alzheimer’s disease (AD). Studies also reveal that anomalous brain copper–cholesterol (Cu–Ch) homeostasis may lead to memory deficits in Swiss albino mice.

Objective: The present study investigates the anti-amnesic potential of clioquinol (5-chloro-7-iodoquinolin-8-ol) in cognitive deficits associated with experimental dementia induced by Cu–Ch.

Materials and methods: Administration of Cu–Ch {0.21?mg/kg, per os – 2% w/v, per os for 8 weeks} was used to induce dementia in Swiss albino mice. The Morris water maze (MWM) test was performed to assess the effect on learning and memory. A battery of biochemical estimations was performed following the MWM test such as brain-reduced glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS), acetylcholinestrase (AChE) activity, and serum cholesterol levels.

Results: Administration of Cu–Ch produced a marked decline in MWM performance measured during the acquisition (78.9?±?3.3) and retrieval trials (9.5?±?2.4), reflecting impairment of learning and memory. Cu–Ch-treated mice also exhibited a marked accentuation of AChE activity (5.8?±?0.55) and TBARS levels (9.74?±?1.9) along with a decline in the GSH level (15.4?±?3.3) and the SOD level (26?±?2.5) when compared with the untreated control group. Administration of clioquinol significantly attenuated Cu–Ch-induced memory deficits and biochemical alterations.

Discussion and conclusion: The findings demonstrate memory restorative ability of clioquinol which may be attributed to its anti-cholinesterase, antioxidative, and cholesterol-lowering potential.     

Experimental hypertension induced vascular dementia: pharmacological, biochemical and behavioral recuperation by angiotensin receptor blocker and acetylcholinesterase inhibitor

Involvement of vascular pathology has been suggested in hypertension as well as vascular dementia (VaD), which also have a very high degree of co-occurrence in ageing population. We have recently reported that experimental diabetes as well as hyperhomocystenemia induces VaD. In the present research work, for the first time we are reporting the genesis of VaD by deoxycorticosterone acetate (DOCA)-salt induced experimental hypertension. Furthermore, we have also investigated the beneficial effect of telmisartan, an angiotensin II type 1 receptor blocker (ARB) and donepezil, an acetylcholinesterase inhibitor (AChEI), on DOCA-salt hypertension induced VaD in rats. DOCA-salt hypertensive rats performed poorly on Morris water maze, reflecting impairment in their learning and memory. Furthermore, DOCA-salt treatment has shown a significant impairment of vascular endothelial function (DOCA attenuated acetylcholine induced endothelium dependent relaxation), with a significant reduction in serum nitrite/nitrate levels, along with increased aortic, serum and brain oxidative stress levels (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and brain acetylcholinesterase activity. Treatments of telmisartan as well as donepezil significantly attenuated DOCA-salt hypertension induced learning and memory deficits, endothelial dysfunction, and changes in various biochemical parameters. It may be concluded that DOCA-salt hypertension induces VaD in rats. ARBs and AChEIs may be considered as potential pharmacological agents for the management of hypertension induced VaD.     

Effect of bis(maltolato) oxovanadium on experimental vascular endothelial dysfunction

The study has been designed to investigate the effect of bis(maltolato) oxovanadium (BMOV), a protein tyrosine phosphatase inhibitor, on hypercholesterolemia and hypertension-induced vascular endothelial dysfunction. High fat diet (8 weeks) and deoxycorticosterone acetate (DOCA; 40 mg kg⁻¹, s.c.) were administered to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure >120 mmHg) respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg⁻¹, p.o.) markedly improved acetylcholine-evoked endothelium-dependent relaxation, lining of vascular endothelium, serum nitrite/nitrate concentration, and serum TBARS in hypercholesterolemic and hypertensive rats. However, this ameliorative effect of BMOV has been prevented by L-NAME (25 mg kg⁻¹, i.p.), an inhibitor of NOS, or by glibenclamide (5 mg kg⁻¹, i.p.), a blocker of ATP-sensitive K⁺ channels. It may be concluded that BMOV-induced inhibition of PTPase may improve vascular endothelial dysfunction.     

Neurotoxic effects of lambda‐cyhalothrin modulated by piperonyl butoxide in the brain of Oreochromis niloticus

The objective of this research was to investigate the neurotoxic effects of pyrethroid pesticide lambda‐cyhalothrin by the modulation of cytochrome P450 with piperonyl butoxide in the brain of juvenile Oreochromis niloticus. The fish were exposed to 0.48 μg L^?1 (1/6 of the 96‐h LC₅₀) lambda‐cyhalothrin and 10 μg L^?1 piperonyl butoxide for 96 h and 15 days. tGSH, GSSG, TBARS contents, GPx, GR, GST, and AChE enzymes activities were determined by spectrophotometrical methods and Hsp70 content was analyzed by ELISA technique. Lambda‐cyhalothrin had no significant effect on the components of GSH redox system, lipid peroxidation and Hsp70 levels but inhibited AChE activity. In the presence of piperonyl butoxide, lambda‐cyhalothrin caused increases in tGSH, GSSG, TBARS and Hsp70 contents, GST activity, and decrease in AChE activity. Present results showed that in the presence of piperonyl butoxide, lambda‐cyhalothrin caused neurotoxic effects by increasing oxidative stress. Adaptation to its oxidative stress effects may be supplied by GSH‐related antioxidant system. Piperonyl butoxide revealed neurotoxic effect of lambda‐cyhalothrin. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1275–1282, 2014.     

Chronic Inhibition of Central Angiotensin-Converting Enzyme Ameliorates Colchicine-Induced Memory Impairment in Mice

Preclinical and clinical studies indicated involvement of the central renin-angiotensin system (RAS) in memory functions. However, the role of central angiotensin-converting enzyme (ACE) in memory function is still unclear. The present study investigated the involvement of central ACE in colchicine-induced memory impairment in the context of cholinergic function and oxidative stress. Memory impairment was induced by intracerebral colchicine administration in mice. The ACE inhibitor, perindopril (0.05 and 0.1 mg/kg/day), was administered orally for 14 days. Memory function was evaluated by the Morris water maze (MWM) test from the 14^th day on after colchicine injection. Donepezil was used as a standard. Parameters of oxidative stress and cholinergic function, ACE activity in serum and the brain were estimated after the completion of behavioral studies. Colchicine caused memory impairment as revealed by no significant change in latency to reach a hidden platform in the MWM test. Furthermore, there was a significant increase in MDA, ROS, and nitrite levels with a reduction in GSH level and acetylcholinesterase (AChE) activity in the brain of colchicine-treated mice. Colchicine significantly increased brain ACE activity without affecting serum ACE. Donepezil prevented colchicine-induced memory impairment in mice. The antidementic effect of perindopril may be attributed to reduced oxidative stress and improvement in cholinergic function. Moreover, the elevated brain ACE activity was also inhibited by perindopril. The study showed that central ACE plays an important role in colchicine-induced memory deficit, corroborating a number of studies that show that treatment with ACE inhibitors could be neuroprotective.     

Enhanced endothelin receptor type B-mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats

Background and Purpose

Normal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin-1 (ET-1) causes vasoconstriction via endothelin receptor type A (ET_AR), but could activate ET_BR in the endothelium and release vasodilator substances. However, the roles of ET_BR in the regulation of vascular function during pregnancy and the vascular mediators involved are unclear.

Experimental Approach

Pressurized mesenteric microvessels from pregnant and virgin Sprague–Dawley rats were loaded with fura-2/AM for simultaneous measurement of diameter and [Ca²⁺]_i.

Key Results

High KCl (51 mM) and phenylephrine (PHE) caused increases in vasoconstriction and [Ca²⁺]_i that were similar in pregnant and virgin rats. ET-1 caused vasoconstriction that was less in pregnant than virgin rats, with small increases in [Ca²⁺]_i. Pretreatment with the ET_BR antagonist BQ-788 caused greater enhancement of ET-1-induced vasoconstriction in pregnant rats. ACh caused endothelium-dependent relaxation and decreased [Ca²⁺]_i, and was more potent in pregnant than in virgin rats. ET-1 + ET_AR antagonist BQ-123, and the ET_BR agonists sarafotoxin 6c (S6c) and IRL-1620 caused greater vasodilation in pregnant than in virgin rats with no changes in [Ca²⁺]_i, suggesting up-regulated ET_BR-mediated relaxation pathways. ACh-, S6c- and IRL-1620-induced relaxation was reduced by the NO synthase inhibitor N_ω-nitro-l-arginine methyl ester, and abolished by tetraethylammonium or endothelium removal. Western blots revealed greater amount of ET_BR in intact microvessels of pregnant than virgin rats, but reduced levels in endothelium-denuded microvessels, supporting a role of endothelial ET_BR.

Conclusions and Implications

The enhanced ET_BR-mediated microvascular relaxation may contribute to the decreased vasoconstriction and vascular resistance during pregnancy.     

Sildenafil improves diabetic vascular activity through suppressing endothelin receptor A, iNOS and NADPH oxidase which is comparable with the endothelin receptor antagonist CPU0213 in STZ-injected rats

Objectives Abnormal vascular activity in diabetes is related not only to impaired nitric oxide bioavailability but also to inflammatory cytokines, endothelin A receptor (ET_A) activation and NADPH oxidase in the vasculature. The potential role of sildenafil in improving vascular function was investigated. Its action was likely blocking upregulated ET_A and NADPH oxidase, and was compared with the endothelin receptor antagonist CPU0213. Methods Diabetes was induced by single‐dose administration of streptozotocin (65 mg/kg, i.p.) to rats and the vascular activity of the thoracic aorta was measured. Key findings An increase in contractile tone to phenylephrine and a decrease in relaxant tone to acetylcholine was found in the thoracic aorta. Oxidative stress was evident by increased malondialdehyde and reduced glutathione peroxidase levels in serum and upregulation of ET_A, MMP‐9 (matrix metalloproteinase‐9), inducible nitric oxide synthase and NADPH oxidase p67^phox were found in the vascular wall. The vascular abnormalities and abnormal biomarkers were attenuated significantly by either sildenafil or CPU0213 along with an improvement of nitric oxide bioavailability and vascular activity. Conclusions Improvement of diabetic vascular abnormal activity by sildenafil results from its suppression of activation of ET_A and NADPH oxidase in the vasculature, and these actions are comparable with those of the endothelin receptor antagonist CPU0213.