Arti Singh

A review on Alzheimer's disease pathophysiology and its management: an update

Alzheimers disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimers disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimers disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing.

A review on mitochondrial restorative mechanism of antioxidants in Alzheimer’s disease and other neurological conditions

Neurodegenerative diseases are intricate in nature because of the involvement of the multiple pathophysiological events including mitochondrial dysfunction, neuroinflammation and oxidative stress. Alzheimer’s disease (AD) is a neurodegenerative disease explained by extracellular amyloid β deposits, intracellular neurofibrillary tangles and mitochondrial dysfunction. Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD. Mitochondrial dysfunction involves alterations in mitochondrial respiratory enzyme complex activities, oxidative stress, opening of permeability transition pore, and enhanced apoptosis. Various bioenergetics and antioxidants have been tried or under different investigational phase against AD and other neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis) because of their complex and multiple site of action. These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified. Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.

Microglial Inhibitory Mechanism of Coenzyme Q10 Against Aβ (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations.

Rationale: Alzheimer’s disease (AD) is a debilitating disease with complex pathophysiology. Amyloid beta (Aβ) (1-42) is a reliable model of AD that recapitulates many aspects of human AD. Objective: The intent of the present study was to investigate the neuroprotective potential of Coenzyme Q10 (CoQ10) and its modulation by minocycline (microglial inhibitor) against Aβ (1-42) induced cognitive dysfunction in rats. Method: Intrahippocampal (i.h.) Aβ (1-42) (1 μg/μl; 4μl/site) were administered followed by drug treatment with galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level, proinflammatory markers (TNF-α), mitochondrial respiratory enzyme complexes (I-IV) and histopathological examinations were assessed. Results: Aβ (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) performance test, causes oxidative stress, raised AChE level, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to sham treatment. Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21 days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ), reduced AChE activity, oxidative damage (reduced LPO, nitrite level and restored SOD, catalase and GHS levels), TNF-α level, restored mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to Aβ (1-42) treated animals. Further, combinations of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulates the protective effect of CoQ10 dose dependently as compared to their effect alone. Conclusion: The present study suggests that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties.

Role of Glutathione-S-transferases in neurological problems

ABSTRACT Introduction: Role of Glutathione-S-transferases (GSTs) has been well explored in the cellular detoxification process, regulation of redox homeostasis and S-glutothionylation of target proteins like JNK, ASK1 etc. However, altered levels or functions of this enzyme or their subtypes have emerged in the development of several pathologies diseases such as Alzheimer’s disease, Parkinson’s disease, cancer and related conditions. Oxidative stress is one of the possible pathological events that contributes significantly to activation of degenerating cascades inside neuronal cells. The central nervous system is highly sensitive to oxidative stress because of low levels or capacities of antioxidant enzymes. The brain is highly metabolic in nature making it susceptible to oxidative stress. Areas covered: The present review provides a comprehensive overview of the multiple connections of GSTs within diverse neurological diseases including cancer. Furthermore, the authors have made significant efforts to discuss the regulation of different GST isoforms that have been associated with various pathological processes such as glioblastoma, Alzheimer’s disease, Parkinson’s disease, stroke and epilepsy. Expert opinion: Though GSTs have been one of the key areas of scientific research over the last few decades, much remains to be elucidated about their physiological functions as well as pathological involvement of GSTs and their polymorphic variants.

Comparative Analysis of Intrahippocampal Amyloid Beta (1-42)and Intracerbroventricular Streptozotocin Models of Alzheimer'sDisease: Possible Behavioral, Biochemical, Mitochondrial, Cellu lar andHistopathological Evidences

Background: Alzheimer’s disease (AD), one of the most common progressive neurodegenerative disorders that leads to dementia in aged humans. Amyloid beta [Aβ (1-42)] model has an ability to mimic many pathological aspects of human AD. Intracerebroventricular streptozotocin (icv-STZ) is an another relevant model for sporadic dementia of Alzheimer’s type. However, both the models are frequently used to AD in experimental animals. Objective: Aim of the present study was to compare these two animal models of AD in order to comment on the best and reliable model of AD as well as screening of the neuroprotectants. Materials and Methods: Animals received a single bilateral intrahippocampal (ih) injection of Aβ (1-42) (1 μg/μl; 4 μl/site) and single bilateral icv injection of STZ (3 mg/kg; 4 μl/site). Galantamine (2 mg/kg) was used as a standard drug and administered for a period of 21 days. Various neurobehavioral parameters were evaluated, followed by biochemical (oxidative stress parameters), molecular (TNF-α level), mitochondrial respiratory enzyme complexes (Complex I, II, III, IV) and histopathological (H&E staining) parameters. Results: In the present study, ih-Aβ (1-42) administration significantly impaired cognitive performance on MWM test, increased oxidative stress markers (raised lipid peroxidation, nitrite concentration, reduced glutathione, catalase activity), increased AChE level and neuroinflammation (increased TNF-α levels), reduced mitochondrial respiratory enzyme complexes (complex I,II,III,IV) and histopathological alterations as compared to single bilateral icv-STZ administration. The effect of galantamine (2 mg/kg) was significantly produced its protective effect in reversing these neurobehavioral, biochemical, cellular and histopathological parameters as compared to their respective controls [ih-Aβ (1-42) and icv-STZ] Conclusions: Result of the present study suggests that the single bilateral ih-Aβ (1-42) model is the most effective and reliable model of AD as compared to single bilateral icv-STZ.

Possible neuroprotective mechanisms of clove oil against icv-colchicine induced cognitive dysfunction

BACKGROUND Alzheimers disease (AD), a common neurodegenerative disorder, recognized to be a major cause of dementia. The aim of the present study was to investigate the neuroprotective mechanisms of clove oil in intracerebroventricular (icv)-colchicine induced cognitive dysfunction in rats. METHODS Single bilateral icv-colchicine (15μg/5μl) was administered, followed by drug treatment with clove oil (0.05ml/kg and 0.1ml/kg, ip), minocycline (25 and 50mg/kg, ip) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level and mitochondrial respiratory enzyme complexes (I-IV) were assessed. RESULTS Colchicine icv administration significantly impaired cognitive performance in Morris water maze (MWM) causes oxidative stress, raised AChE level, caused neuroinflammation and mitochondrial dysfunction as compared to sham treatment. Treatment with clove oil (0.05ml/kg and 0.1ml/kg) and minocycline (25 and 50mg/kg) alone significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ) in MWM task, reduced AChE activity, oxidative damage (reduced lipid peroxidation levels, nitrite level and restored glutathione levels) and restored mitochondrial respiratory enzyme complex (I-IV) activities as compared to icv-colchicine treatment. Further, combinations of clove oil (0.1ml/kg) with minocycline (50mg/kg) significantly modulate the neuroprotective effect of clove oil as compared to their effect alone. CONCLUSION The present study highlights that the major neuroprotective effect of clove oil due to its mitochondrial restoring and anti-oxidant properties along with a microglial inhibitory mechanism.

Neuropathic Pain models caused by damage to central or peripheral nervous system

Neuropathic Pain (NP) is a painful condition which is a direct consequence of a lesion or disease affecting the somatosensory system with symptoms like allodynia, hyperalgesia. It has complex pathogenesis as it involves several molecular signaling pathways, thus numerous reliable animal models are crucial to understand the underlying mechanism of NP and formulate effective management therapy. Some models like spinal cord injury, chronic constriction injury, spinal nerve ligation, chemotherapy induced peripheral neuropathy, diabetes-induced NP and many more are discussed. This review contains an overview of the procedures followed to induce neuropathy and specific characteristics of that particular model. Some new techniques like spared nerve ligation, have omitted the limitation of methods not presently used where complete nerve damage occurs. Since animal models provide a window to experienced symptoms and physiology and impact the translation of bench discoveries to the bedside, the reporting, interpretation and comparison of these models is necessary because slight variation in procedure of model generation can drastically alter the results. The development of novel, but rational analgesic drugs to alleviate this intractable pain demands elucidation of molecular mechanisms of NP for which different types of animal models have been established.

Galantamine potentiates neuroprotective potential of Taurine in Aβ (1-42) induced animal model of Alzheimer′s disease: The synergistic role of GABAA & α 7 nicotinic acetylcholine receptors

I biomarker of Alzheimer disease (AD) does not exist yet. Cerebrospinal fluid (CSF) levels of amyloid β 1-42 (Aβ 1-42), τ and phospho-τ are often used standards (senzitivity > 85% and specificity > 75-85% are expected for a good biomarker). We evaluated new biomarkers based on interactions of Aβ and its intracellular binding partners (mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) and τ) and on abilities of amyloid peptides/proteins to oligomerize/ aggregate. In young patients with neuroinflammatry diseases, no changes in Aβ were found. Increased concentrations of 17β-HSD10 were observed only in people with multiple sclerosis in later stages probably as a compensatory response to attacts of immune system. In old patients with neuroinflammatory diseases, changes in Aβ (but not in τ/phospho-τ or 17β-HSD10) were similar to those in AD. Results can be interpreted by ageand neuroinflammation-dependent alterations in extracellular Aβ and a key role of Aβ in interactions. Changes observed in MCI-AD (Aβ, τ/phospho-τ, Aβ – τ complexes, 17β-HSD10, thioflavinT-based to intrinsic amyloid fluorescence signals ratio) were similar to those in AD. Results suggest early changes in intracellular Aβ and accumulations of amyloid peptides/proteins in the brain, in addition to increased oligomerization/ aggregation. Both fluorescences are probably based on different amyloid structures (ThioflavinT-based on oligomers, instrinsic amyloid fluorescence on aggregates partly accumulated in the brain). Characteristic of new biomarkers of AD are as follows: Aβ – τ complexes (senzitivity 68.6% and specificity 73.3%), 17β-HSD10 (80.0% and 73.3%), 17β-HSD10 – Aβ complexes (66.7% and 68.8%), ThioflavinT-based to intrinsic amyloid fluorescence signals ratio (61.1% and 70.8%).