Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease.

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-ß (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aß and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aß (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aß (1-42) level, GSK-3ß activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

Protective effects of alendronate in Triton X-100-induced hyperlipidemia in rats.

BACKGROUND/AIMS: The aim of the present study was to evaluate the protective effects of alendronate (used in osteoporosis disease) in Triton X-100 (a polyethylene glycol-based non-ionic surfactant)-induced hyperlipidemia in rats. MATERIALS AND METHODS: The animals were randomized into seven groups receiving different treatments for 21 days, and alendronate was administered (1.5 and 3 mg/kg body weight, per orally (p.o.) by oral gavage). On day 21, the rats were anesthetized and decapitated, blood samples were extracted, and the livers were dissected for various biochemical tests and histopathological examinations. RESULTS: The biochemical parameters, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C), thiobarbituric acid reactive substances (TBARS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and atherogenic index, were increased, and reduction in high-density lipoprotein-cholesterol (HDL-C) levels was observed following Triton X-100 treatment to rats. Alendronate (1.5 and 3 mg/kg) produced a dose-dependent reduction in serum TC, VLDL-C, TGs, ratio of TC/HDL-C, ALT, AST, and TBARS. It significantly increased the HDL-C and superoxide dismutase levels but did not cause a significant decrease in serum LDL-C and/or an increase in catalase levels. Histopathological examinations of alendronate showed beneficial effects with lower capsular thickening, slight enlargement of the hepatocytes at the margin, and lower inflammatory cell infiltration. CONCLUSION: Alendronate showed dose-dependent antihyperlipidemic and hepatoprotective effects. It may serve a dual purpose as anti-osteoporotic and hypolipidemic by reducing blood cholesterol and TG synthesis and offering hepatic protection.

Ameliorative effect of alendronate against intracerebroventricular streptozotocin induced alteration in neurobehavioral, neuroinflammation and biochemical parameters with emphasis on Aß and BACE-1.

Alzheimer's disease (AD) is the most prevalent age related neurodegenerative disorder manifested by progressive cognitive decline and neuronal loss in the brain, yet precise etiopathology of majority of sporadic or late-onset AD cases is unknown. AD is associated with various pathological events such as Aß deposition due to BACE-1 induced cleavage of APP, neuroinflammation, increased cholesterol synthesis, cholinergic deficit and oxidative stress. It was found that bone drug, alendronate (ALN) that cross blood brain barrier inhibits brain cholesterol synthesis and AChE enzyme activity. As cholesterol modifying agents have been supposed to alter AD like pathologies, the current study was designed to investigate the possible neuroprotective and therapeutic potential of ALN against ICV STZ induced experimental sporadic AD (SAD) in mice in a non-cholesterol dependent manner, using donepezil (5 mg/kg) as a reference standard. The preliminary study was done by molecular modelling to identify the binding affinity of ALN with BACE-1 in silico. The prevention of cognitive impairment in mice induced by ICV STZ (3 mg/kg) infused on first and third day, by ALN (1.76 mg/kg p.o.) administered for 15 consecutive days was assessed through Spontaneous Alternation Behavior (SAB) and Morris water maze (MWM) test. Additionally, the protective effect of ALN was also observed by the reversal of altered levels of Aß1-42, BACE-,1 neuroinflammatory cytokines, AChE activity and oxidative stress markers (except TBARS) in ICV-STZ infused mice. However, the findings of the present study imply the therapeutic potential of ALN against SAD-like complications.

Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Aß peptides in animal model of Alzheimer's disease.

With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-ß (1-42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aß (1-42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aß (1-42) level, IRS-S307 activity, GSK-3ß activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD.

Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats.

Vascular dementia (VaD) is the second most common form of senile dementia, embraces memory deficits, neuroinflammation, executive function damage, mood and behavioral changes and abnormal cerebral blood flow. The purpose of the study was to explore the therapeutic potential of betulinic acid in bilateral common carotid artery occlusion (BCCAO) induced VaD in experimental rats. VaD was induced by BCCAO in rats and betulinic acid (10 and 15 mg/kg/day po) was administered 1 week after surgery. The cerebral blood pressure of the animal was recorded before and after the treatment using Laser Doppler flow meter. Object recognition task for non-spatial, Morris water maze for spatial and locomotor activity was performed to evaluate behavioral changes in rats. At the end of the study, animals were decapitated and hippocampus was separated to perform biochemical, neuroinflammatory and second messengers cAMP/cGMP analysis. Histology was done to study the brain pathophysiology. BCCAO surgery was able to significantly impaired memory in rats as observed behavioral and biochemical parameters. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA was able to re-establish cerebral blood flow, restore behavioral parameters and showed significant improvements in the as cAMP,cGMP and BDNF levels, restrain the oxidative stress and inflammatory parameters. In histopathology, betulinic acid treated groups showed a decrease in microgliosis and less pathological abnormalities comparable to diseased rat's brain. The observed effect might be attributed to the neuroprotective potential of betulinic acid and its ability to restore cognitive impairment and hippocampal neurochemistry in VaD.

Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism.

BACKGROUND: The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats. METHODS: STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1ß, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis. RESULTS: STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain. CONCLUSIONS: The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.

Gastroprotective Effect of Thymoquinone on Water Immersion Restraint Stress Induced Ulceration in Rats.

To evaluated the role of thymoquinone (TQ) on stress induced ulceration progress in rats subjected to water immersion restraint as a stress (WRS) condition model. Wistar albino rats were divided into different groups; the animals were subjected to WRS. TQ (10 mg/kg) alone and TQ with ranitidine (20 mg/kg) were administered per orally as pre treatment for 7 days. On 8th day the animals were sacrificed, gastric juice, pH, acid secretion, acid output, ulcer index and markers of oxidative stress and histopathology were determined. Volume of gastric juice, acid secretion was increased, while pH decreased in WRS animals. TQ pre-treated group showed reduction in the above parameters. The combination group showed more significant results than TQ and ranitidine alone on the above parameters. TQ decreased the ulcer index (UI), again combination group showed more significant decreased in UI. Oxidative stress markers were reduced and antioxidant enzymes were augmented. Gastric mucosa was protected as demonstrated by histological slides. The present study is one of its kinds to demonstrate anti ulcer effect of TQ against the water immersion restraint method of stress ulceration. Thus, TQ has the potential to be the promising drug for stress induced gastric ulcers.

Caffeic acid attenuates oxidative stress, learning and memory deficit in intra-cerebroventricular streptozotocin induced experimental dementia in rats.

Oxidative stress has been implicated in cognitive decline as seen during normal aging and in sporadic Alzheimer's disease (AD). Caffeic acid, a polyphenolic compound, has been reported to possess potent antioxidant and neuroprotective properties. The role of caffeic acid in experimental dementia is not fully understood. Thus the present study was designed to investigate the therapeutic potential of caffeic acid in streptozotocin (STZ)-induced experimental dementia of Alzheimer's type in rats. Streptozotocin (STZ) was administered intracerebroventrically (ICV) on day 1 and 3 (3mg/kg, ICV bilaterally) in Wistar rats. Caffeic acid was administered (10, 20 and 40mg/kg/day p.o.) 1h following STZ infusion upto 21st day. Morris water maze and object recognition task were used to assess learning and memory in rats. Terminally, acetylcholinesterase (AChE) activity and the levels of oxido-nitrosative stress markers were determined in cortical and hippocampal brain regions of rats. STZ produced significant (p<0.001) learning and memory impairment, oxido-nitrosative stress and cholinergic deficit in rats. Whereas, caffeic acid treatment significantly (p<0.001) and dose dependently attenuated STZ induced behavioral and biochemical abnormalities in rats. The observed cognitive improvement following caffeic acid in STZ treated rats may be due to its antioxidant activity and restoration of cholinergic functions. Our results suggest the therapeutic potential of caffeic acid in cognitive disorders such as AD.

Pharmacological induction of hemeoxygenase-1 activity attenuates intracerebroventricular streptozotocin induced neurocognitive deficit and oxidative stress in rats.

Under conditions of oxidative stress associated with neurodegenerative disorders, alterations in hemeoxygenase-1 (HO-1) activity have been reported. In the present study we have investigated the role of HO-1 pathway in intracerebroventricular (ICV) streptozotocin (STZ) induced neurocognitive deficits and oxidative stress in rats. STZ was infused ICV bilaterally (3mg/Kg) on the alternate days in rats. Hemin was used as a pharmacological inducer of HO-1 activity and tin-protoporphyrin (SnPP) as HO-1 inhibitor. Hemin was administered with or without SnPP from day to 21 following 1st STZ infusion in rats. The cognitive functions were assessed by Morris water maze (MWM) and object recognition task (ORT) in rats. Biochemically, rat hippocampal and cortical brain homogenate was used to assess the levels of oxidative stress markers and acetylcholinesterase and HO-1 activity. Infusion of STZ caused significant elevation HO-1 activity on day 7 following 1st STZ infusion, however it was decreased on day 21, indicating its oxidative modification. Hemin caused significant elevation in HO-1 activity and attenuated STZ-induced oxidative stress. Moreover, hemin restored acetylcholinesterase activity and cognitive functions in STZ infused rats. Pre-administration of SnPP completely abrogated beneficial effects of hemin in STZ rats, indicating HO-1 dependency. The observed beneficial effects of hemin on spatial memory may be due to its ability to favorably modulate HO-1 pathway and antioxidant mechanisms.

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer's disease.

Cyclic nucleotides viz., cAMP/cGMP has been well known to play important role in cellular function and deficiency in their levels has been implicated in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Phosphodiesterases (PDE) are the enzymes involved in the metabolism of cyclic nucleotides and the inhibition of phosphodiesterases is considered to be viable strategy to restore the level of cyclic nucleotides and their functions in the brain. Various synthetic PDE inhibitors had been used clinically for various disorders and also suggested to be useful candidates for treating neurological disorders. However, side effects of these synthetic PDE inhibitors have limited their use in clinical practice. Natural plant extracts or their bio-active compounds are considered to be safe and are widely acceptable. During the last decade, many plant extracts or their bio-active compounds were tested pre-clinically for PDE inhibitory activity and are reported to be equally potent in inhibiting PDE's, as that of synthetic compounds. The present review is aimed to discuss the potential plant extract/compounds with PDE inhibitory activity and critically discuss their potential role in Alzheimer's disease.