Varun Gupta

A review on animal models of stroke: An update

Stroke is one of the major healthcare challenges prevailing across the globe due to its significant rate of mortality and morbidity. Stroke is multifactorial in nature and involves several cellular and molecular signaling cascades that make the pathogenesis complex and treatment difficult. For a deeper understanding of the diverse pathological mechanisms and molecular & cellular cascades during stroke, animal modeling serves as a reliable and an effective tool. This also helps to develop and critically analyse various neuroprotective strategies for the mitigation of this devastating disease. Animal modeling for stroke has been revolutionized with the development of newer and more relevant models or approaches that mimic the clinical setting of stroke to a greater extent. This review analyses experimental models of stroke (ischemic and hemorrhagic) and their reliability in stroke situation. Besides this, the review also stresses upon the use of various preclinical models to understand the pathophysiological mechanisms that operate during stroke and to elucidate new, safe and effective neuroprotective agents to combat this life threatening healthcare concern.

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.

Haemoptysis associated with gatifloxacin in a 27 year old male asthmatic--a case report.

Gatifloxacin is a 8-methoxyfluoroquinolone antimicrobial with an extended spectrum of antimicrobial activity. It was approved for use in the United States in 1999 and was introduced in India in October 2001. The drug is approved for use in the treatment of various respiratory infections including bronchitis, urinary tract infections and gonorrhoea [1]. We report a case of haemoptysis associated with gatifloxacin. A 27 year old male patient, known to have bronchial asthma which was well controlled, attended the Respiratory and Chest Diseases outpatient department with the complaint of frank blood in the sputum. He had had a cough and mucopurulent sputum for the last 10 days. On the fourth day of cough he took gatifloxacin 400 mg (Gatikind, Mankind India) once daily (self medication being a doctor) for 5 days. The symptoms of cough and sputum improved but he had a bout of frank haemoptysis on the fifth day of the treatment for which he presented to the physician. The drug was stopped and thereafter, no episode of haemoptyis occurred. There was no history of violent coughing or any concomitant medication. On examination bilateral breath sounds were present and no added sounds were heard. Spirometry was performed and FEV1 was found to be more than 80% of the predicted value. The chest X-ray showed no significant finding. Bleeding and clotting times were in the normal range. Complete blood count was not available. The diagnosis of bronchitis was made as the patient had symptoms consistent with upper respiratory tract infection and normal chest radiograph [2]. There was no history of gatifloxacin intake in the past. The patient provided written informed consent for publication of this report. The case was reported to the zonal centre under the national pharmacovigilance programme. Although bronchitis is a common cause of haemoptysis [2], in this case the event surfaced when the symptoms of bronchitis were improving. The temporal relationship between the administration of gatifloxacin with the occurrence of the event, and no further episode of haemoptysis on stopping the drug, also supports that the event could be due to gatifloxacin. There are reports suggesting occurrence of haemorrhage with gatifloxacin [3] and increased risk of bleeding with the concomitant use of warfarin and gatifloxacin [4, 5]. The strength of association was examined using the Naranjos Adverse Drug Reaction Probability Scale, in which a score of +4 was obtained suggesting a ‘possible’ link. The Naranjos algorithm defines adverse reactions as definite (score > 9), probable (score between 5 and 8), possible (1–4) and doubtful (<1) [6]. There could be several possible explanations for gatifloxacin associated haemoptysis. Infection in bronchitis causes superficial mucosal inflammation and oedema which can lead to the rupture of the superficial blood vessels. Gatifloxacin is widely distributed throughout the body into many body tissues and fluids. Rapid distribution of gatifloxacin into tissues also results in high concentrations of gatifloxacin in the respiratory system including the bronchial mucosa [3]. This could probably increase the inflammation of the mucosal cells. This effect coupled with the drugs characteristic to interfere with the coagulation cascade [4, 5] may explain haemoptysis associated with gatifloxacin in patients of bronchitis. This hypothesis needs to be further tested. In conclusion, gatifloxacin has been approved for use in bronchitis because of its enhanced activity against the respiratory pathogens and high concentration in the respiratory tract [3, 7]. However, in the view of this patient (a doctor) and in the light of previously reported cases of haemorrhage, its use in bronchitis needs to be monitored carefully.

Discovery of Neuroprotective Antioxidants for the Management of Ischemic Brain Stroke

Abstract Nowadays, ischemic brain stroke is one of the most devastating and lethal problems in our society. Being the second leading cause of death worldwide, it is a prime healthcare concern in almost all demographic zones. The survivors of stroke have physical disability, motor dysfunction, poststroke depression, and memory impairment, which exert deteriorating effects on their quality of life. The pathophysiology of stroke is complex involving several cellular and molecular events that are poorly understood so far. The currently available drug therapy is inadequate to treat this problem and needs further treatment options because of its narrow safety window. Therefore several neuroprotective approaches including antioxidant drugs are being tested to treat this complex problem with the aim to target multiple pathways responsible for it. The involvement of oxidative stress, neuroinflammation, apoptosis, and microglial activation are few of the major proposed cellular cascades that precipitate stroke pathology. This chapter spotlights on targeting these mechanisms by using various neuroprotective drugs. Many neuroprotectants including antioxidants such as ginseng, naringin, and hesperidine are being studied in various preclinical and clinical phases to treat stroke and related problems and amongst those, a few drugs have been successfully proved to have significant tendency of neuroprotection. The use of these drugs in the clinical setting may prove to be a pioneering answer to the severely distressing conditions of mortality and morbidity in stroke. Hence, the present chapter deals with various neuroprotectants targeting oxidative stress and related cascades to treat stroke and related problems.

Preclinical Explorative Assessment of Dimethyl Fumarate-Based Biocompatible Nanolipoidal Carriers for the Management of Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease in which myelin sheath damage occurs due to internal and external factors. MS especially affects the young population. Dimethyl fumarate (DMF) is a promising agent for MS treatment, although it is associated with concerns such as poor brain permeation, multiple dosing, and gastrointestinal flushing. The present study attempts to evaluate the preclinical performance of specially designed DMF-based lipoidal nanoparticles in a cuprizone-induced demyelination model in rodents. The studies proved the efficacy of lipid-based nanoparticles containing DMF in a once-a-day dosage regimen over that of thrice-a-day plain DMF administration on crucial parameters like motor coordination, grip strength, mortality, body weight, and locomotor activity. However, neither blank lipid nor blank neuroprotective (vitamins A, D, and E) loaded nanoparticles were able to elicit any desirable behavioral response. Histopathological studies showed that the designed once-a-day DMF nanomedicines were well tolerated and rejuvenated the myelin sheath vis-à-vis the plain DMF thrice-a-day regimen. These findings provide proof of concept for a biocompatible nanomedicine for MS with tremendous promise for effective brain delivery and patient compliance on the grounds of a reduction in the dosage frequency.

Numerical Treatments For The Space- Time Fractional Fokker- Planck Equation By Means of Homotopy Perturbation Natural Transform Method

In the present paper, an efficient approach based on homotopy perturbation method by using natural transform is adopted to solve some linear and non-linear space-time fractional Fokker-Planck Equations (FPE) in closed form. The space and time fractional derivatives are considered in Caputo sense. The homotopy perturbation natural transform method is a combined form of natural transform, homotopy perturbation method and Hes polynomials. The method gives an analytical solution in the form of a convergent series with easily computable components, requiring no linearization or small perturbation. The numerical result shows the effectiveness and good accuracy of the method. Keywords: Fokker-Planck Equation, Caputo fractional derivative, Natural transform, Homotopy perturbation method.