Rahul Deshmukh

Alzheimer's disease: Is this a brain specific diabetic condition?

Alzheimers disease (AD) and type 2 diabetes (T2DM) are the two major health issues affecting millions of elderly people worldwide, with major impacts in the patients daily life. Numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The principal biological mechanisms that associate with the progression of diabetes and AD are not completely understood. Impaired insulin signaling, uncontrolled glucose metabolism, oxidative stress, abnormal protein processing, and the stimulation of inflammatory pathways are common features to both AD and T2DM. In recent years brain specific abnormalities in insulin and insulin like growth factor (IGF) signaling considered as a major trigger involved in the etiopathogenesis of AD, showing T2DM like milieu. This review summarizes the pathways that might link diabetes and AD and the effect of diminished insulin.

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 Alzheimers 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 Alzheimers 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.

Tetrabenazine: Spotlight on Drug Review.

Background: Tetrabenazine (TBZ) is the only US Food and Drug Administration-approved drug for the treatment of chorea related to Huntingtons disease and other hyperkinetic disorders. TBZ was first synthesized in 1950, and was then used for the treatment of psychosis. But later its potential in treating hyperkinetic disorders was proved by its ability to block vesicular monoamine transporters 2 and deplete monoamine stores. There is still lack of awareness about the therapeutic potential of this drug. Summary: TBZ had been approved only for the treatment of chorea, but several clinical studies have been conducted by different research groups and it was concluded that TBZ is effective in various other conditions such as tardive dyskinesia, dystonia, tics, and Tourettes syndrome, thus, highlighting the need for further clinical trials in these conditions. Key Message: The intention of this review is to sum up the information regarding chemistry, mechanism of action, pharmacokinetics, interactions, contraindications, adverse effects, and clinical efficacy of TBZ in diseases other than Huntingtons chorea.

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.

Sertraline and venlafaxine improves motor performance and neurobehavioral deficit in quinolinic acid induced Huntington’s like symptoms in rats: Possible neurotransmitters modulation

BACKGROUNDnHuntington Disease is autosomal, fatal and progressive neurodegenerative disorder for which clinically available drugs offer only symptomatic relief. Emerging strides have indicated that antidepressants improve motor performance, restore neurotransmitters level, ameliorates striatal atrophy, increases BDNF level and may enhance neurogenesis. Therefore, we investigated sertraline and venlafaxine, clinically available drugs for depression with numerous neuroprotective properties, for their beneficial effects, if any, in quinolinic acid induced Huntingtons like symptoms in rats.nnnMETHODSnRats were administered quinolinic acid (QA) (200 nmol/2μl saline) intrastriatal bilaterally on 0day. Sertraline and venlafaxine (10 and 20mg/kg, po) each were administered for 21days once a day. Motor performance was assessed using rotarod test, grip strength test, narrow beam walk test on weekly basis. On day 22, animals were sacrificed and rat striatum was isolated for biochemical (LPO, GSH and Nitrite), neuroinflammation (TNF-α, IL-1β and IL-6) and neurochemical analysis (GABA, glutamate, norepinephrine, dopamine, serotonin, DOPAC, HVA and 5-HIAA).nnnRESULTSnQA treatment significantly altered body weight, motor performance, oxidative defense (increased LPO, nitrite and decreased GSH), pro-inflammatory cytokines levels (TNF-α, IL-6 and IL-1β), neurochemical level (GABA, glutamate, nor-epinephrine, dopamine, serotonin, HVA, DOPAC, 5-HIAA). Sertraline and venlafaxine at selected doses significantly attenuated QA induced alterations in striatum.nnnCONCLUSIONnThe present study suggests that modulation of monoamines level, normalization of GABA and glutamatergic signaling, anti-oxidant and anti-inflammatory properties could underlie the neuroprotective effect of sertraline and venlafaxine in QA induced Huntingtons like symptoms.

Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease

Alzheimers disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD.

Lupeol Isolated from Betula alnoides Ameliorates Amyloid Beta Induced Neuronal Damage via Targeting VariousPathological Events and Alteration in Neurotransmitter Levels in Ratâs Brain

Lupeol, a natural active constituent of Betula alnoides (BA), is well known for its anti-inflammatory, anti-oxidant and neuroprotective activities. In present study the therapeutic potential of lupeol was investigated against amyloid beta (Aβ (1-42)) induced cognitive deficit, neurochemical and biochemical abnormalities in rats. Lupeol was isolated from the BA and its structure was confirmed through nuclear magnetic resonance spectra. Aβ (1-42) (4 μg/4 μL) intracerebroventrically (icv) was administered to rats for the induction of Alzheimers disease (AD). Lupeol treatment (25 mg/kg/day, 50 mg/kg/day and 100 mg/kg/day per orally) was started one week after Aβ (1-42) infusion up to the 21st days. Morris water maze from day 16 to 21 and object recognition tasks on day 14 and 15 were performed for memory assessment. On 22nd day, animals were sacrificed and hippocampi were isolated for analysis of biochemical (acetylcholinesterase, lipid hydroperoxide, glutathione and nitrite) and neuro-inflammatory (tumor necrosis factor -α, interleukin (IL)-1β, and IL-6) parameters. In the present study Aβ (1-42) infusion was significantly impaired behavioral memory, increased oxidative stress, decreased antioxidant enzyme and increased pro-inflammatory markers. Treatment of lupeol significantly restored Aβ (1-42) induced behavioral and biochemical abnormalities in rats brain. The findings of the present study suggest that lupeol act through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders of AD.

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 Alzheimers 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 PDEs, 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 Alzheimers disease.

Neuroprotective potential of spermidine against rotenone induced Parkinson's disease in rats

ABSTRACT Parkinsons disease is a leading hypokinetic disorder characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of mid‐brain. Degeneration of dopaminergic neurons is considered to be due to oxidative stress, neuroinflammation, disturbed calcium homeostasis and glutamate excitotoxicity etc. Spermidine is a polyamine which counteracts age associated cell death by scavenging free radical formation, activates authophagic machinery by enhancing formation of autophagosome, and antagonizes NMDA receptor. In the current study we investigated the neuroprotective potential of spermidine against rotenone induced PD in rats. Rats were treated subcutaneously with rotenone 1.5mg/kg daily for 28 days. Spermidine 5&10mg/kg was administered orally 1h prior to rotenone administration from 15 to 28. Rotenone caused significant reduction in motor functioning and elevated levels of oxidative stress markers and proinflammatory cytokines levels (IL‐1&bgr;, IL6 and TNF‐&agr;). The neurochemical analysis revealed a significant decrease in serotonin, norepinephrine, dopamine and their metabolites accompanied by a significant loss of dopaminergic neurons in the SNpc following ROT injection. However, treatment with spermidine rescued DAergic neurons in SNpc and nerve terminals in the striatum following ROT insult. Spermidine treatment also attenuated oxidative stress, neuroinflammation and restored striatal neurochemistry. Results of our study suggest that spermidine has promising neuroprotective effect against degenerative changes in experimental PD, and the protective effects are mediated through its antioxidant and anti‐inflammatory properties. HIGHLIGHTSRotenone induces motor impairment in rats and cause striatal neurochemical alterations.Spermidine is a polyamine attenuates rotenone induced movement disabilities.Spermidine produces antioxidant effect and improves striatal dopamine levels.

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

BACKGROUNDnThe purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats.nnnMETHODSnSTZ (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-1β, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis.nnnRESULTSnSTZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokines 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.nnnCONCLUSIONSnThe 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.