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There have been reports of neurodegenerative diseases including Parkinsonism, Alzheimer’s disease and Creutzfeldt Jakob disease following COVID-19. The exact pathogenesis of these has not been elucidated yet though authors have proposed the possibility of the hyper-inflammatory state of COVID-19 acting as a trigger through cytokine-induced inflammatory response of brain microglia and astrocytes, as well as damage resulting from the central nervous system hypoxia of severe COVID-19, or even the direct pathogenetic actions of SARS-CoV-2 on the brain. There have also been reports of worsening of Parkinsonian symptoms, new onset movement disorders and even rapidly progressive dementia following COVID-19 vaccination using different vaccine types. The occurrence of protein-aggregation mediated neurodegenerative syndromes following both COVID-19 and vaccination led us to explore the common thread of the Spike (S) protein as a potential mediator. In the current study, we investigated the interactions of S protein of SARS-CoV-2 with α-synuclein.

Subhasish Pramanik,1 Lakshmi Kanta Mondal,2 Suman Kalyan Paine,3 Sneha Jain,2 Subhankar Chowdhury,1 Upasana Ganguly,4 Sayantan Ghosh,2 Chiranjit Bose,1 Koena Bhattacharjee,2 Gautam Bhaduri5 1Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata, 700020, India; 2Regional Institute of Ophthalmology (RIO), Medical College and Hospital, Kolkata, 700073, India; 3National Institute of Biomedical Genomics (NIBMG), Kalyani, West Bengal, India; 4Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Haryana, India; 5MGM Medical College, Kishanganj, Bihar, IndiaCorrespondence: Lakshmi Kanta MondalRegional Institute of Ophthalmology, Medical College, Kolkata, IndiaTel +91 9830830216Email Lakshmi.mondal62@gmail.comPurpose: In the present study, we aimed to evaluate the efficacy, safety, and cost-effectiveness of the anti-vascular endothelial growth factor (anti-VEGF), namely ranibizumab (RBZ) or bevacizumab (BVZ), after either focal or grid or scatter laser photocoagulation, for the treatment of diabetic macular edema (DME) in the Indian population.Methods: Retrospective data were collected in the Regional Institute of Ophthalmology, Kolkata, India between January 2018 and June 2019. Seventy-seven eyes received 3 consecutive monthly intravitreal injections of RBZ (0.5 mg) and were followed by prompt laser photocoagulation (within 7– 10 days after the third injection). Similarly, 51 eyes received 3 consecutive monthly intravitreal injections of BVZ (1.25 mg), an off-label drug, and were followed by prompt laser therapy. Safety assessments of the therapy, as well as surrogate markers of biochemical derangements related to diabetic retinopathy (DR), were also investigated at the end of 12 months.Results: Seventy-seven subjects who were given a treatment of RBZ+laser therapy showed average 6.87± 5.53 letters gain in their best-corrected visual acuity (BCVA) score, whereas the ones treated with off-label BVZ+ laser therapy demonstrated improvement in BCVA of an average 6.82± 5.76 letters in “Early Treatment Diabetic Retinopathy Study” (ETDRS) chart. The study also highlights the cost-effectiveness of both RBZ+laser and BVZ+laser therapies for the treatment of DME in DR. The results demonstrated that a subject has to pay 20.951 times more cost (in INR) for RBZ+laser therapy compared to BVZ+laser therapy, to get an almost similar outcome.Conclusion: BVZ is found to be the more attractive option for treating DME in DR for its cost-friendliness over RBZ in terms of BCVA outcome, as well as the safety perspectives, at least for the economically backward population in developing countries, like India.Keywords: diabetic retinopathy, diabetic macular edema, ranibizumab, bevacizumab, laser therapy, cost-effectiveness

The toxicity of accumulated α-synuclein plays a key role in the neurodegeneration of Parkinson's disease (PD). This study has demonstrated that iron in varying concentrations (up to 400 µM) causes an increase in α-synuclein content in SH-SY5Y cells associated with mitochondrial depolarization, decreased cellular ATP content and loss of cell viability during incubation up to 96 h. Knocking-down α-synuclein expression prevents cytotoxic actions of iron, which can also be prevented by cyclosporine A (a blocker of mitochondrial permeability transition pore). These results indicate that iron cytotoxicity is mediated by α-synuclein acting on mitochondria. Likewise siRNA mediated knock-down of Parkin causes an accumulation of α-synuclein accompanied by mitochondrial dysfunction and cell death during 48 h incubation under basal conditions, but these changes are not further aggravated by co-incubation with iron (400 µM). We have also analyzed mitochondrial dysfunction and cell viability in SH-SY5Y cells under double knock-down (α-synuclein and Parkin concurrently) conditions during incubation for 48 h with or without iron. Our results tend to suggest that iron inactivates Parkin in SH-SY5Y cells and thereby inhibits the proteasomal degradation of α-synuclein, and the accumulated α-synuclein causes mitochondrial dysfunction and cell death. These results have implications in the pathogenesis of sporadic PD and also familial type with Parkin mutations.

Ferroptosis has been characterized over the last few years as a form of iron-dependent regulated cell death which is accompanied by an accumulation of reactive oxygen species and lipid oxidation products inside the cells along with typical morphological alterations in mitochondria. Ferroptosis is inhibited by specific inhibitors called ferrostatin-1 and liproxstatin-1, apart from iron-chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially with regard to the involvement of mitochondria in the final execution of ferroptotic death. This study uses two typical inducers of ferroptosis such as erastin and ferric ammonium citrate on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of reactive oxygen species and malondialdehyde as well as a depletion of reduced glutathione. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin or ferric ammonium citrate, implying the crucial role of mitochondrial permeability transition pore activation in ferroptotic death. Under our experimental conditions, it is also observed that the late-phase production of reactive oxygen species is inhibited by cyclosporine A.

Parkinson's disease (PD) is a neurodegenerative disorder characterized classically by motor manifestations. However, nonmotor symptoms appear early in the course of the disease progression, making both diagnosis and treatment difficult. The pathology of PD is complicated by the accumulation and aggregation of misfolded proteins in intracellular cytoplasmic inclusions called Lewy bodies (LBs). The main toxic component of LBs is the protein α-Synuclein which plays a pivotal role in PD pathogenesis. α-Synuclein can propagate from cell-to-cell exhibiting prion-like properties and spread PD pathology throughout the central nervous system. Immunotherapeutic interventions in PD, both active and passive immunization, have targeted α-Synuclein in both experimental models and clinical trials. In addition, targeting the hyperactive inflammation in PD also holds promise in designing potential immunotherapeutics. The inflammatory and proteotoxic pathways are interlinked and contribute immensely to the disease pathology. In this chapter, we critically review the targets of immunotherapeutic interventions in PD, focusing on the pathogenetic mechanisms of PD, particularly neuroinflammation and α-Synuclein misfolding, aggregation, and propagation. We thoroughly summarized the various immunotherapeutic strategies designed to treat PD-in vitro, in vivo, and clinical trials. The development of these targeted immunotherapies could open a new avenue in the treatment of patients with PD.

COVID-19 mortality and spread have varied widely across countries. It has been quite difficult to explain this variability by restrictive strategies adopted in the different nations. A significant part of this variation may be dependent on biological and environmental factors. In early April we had predicted a low mortality due to COVID-19 in India based on several factors, cross-immunity to endemic coronaviruses being prominent among them. Cross-reactive antibodies as well as T-cells have been later demonstrated by several groups. The importance of this cross-immunity in modifying the spread of COVID-19 in a population and the development of herd immunity has been discussed by us, as well as other authors who in a recent review have elaborated several theoretical models. Other driving factors of this natural variation of COVID severity may be trained immunity and immune tolerance acquired by the innate immune system, both a result of recurrent infections by diverse pathogens. We hypothesize, that in countries like India, huge sections of population, living in crowded and unsatisfactory hygienic conditions, are subjected to repeated infections by viruses, bacteria, and eukaryotic parasites, and this probably leads to a state of 'immune tolerance' in them against a novel organism like SARS-CoV-2. Although at present the major focus is on the detection and containment of COVID-19, including the development of vaccines, it appears that a better understanding of the host's response to SARS-CoV-2 invasion may provide us clues to explain the epidemiology of this pandemic in different countries and formulate nation-specific management plans. This article is protected by copyright. All rights reserved.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.

The development of neuroprotective drugs targeting mitochondria could be an important strategy in combating the progressive clinical course of Parkinson's disease. In the current study, we demonstrated that in SH-SY5Y cells (human dopaminergic neuroblastoma cell line), rotenone caused a dose-dependent (0.25-1 μM) and time-dependent (up to 48 h) loss of cell viability and a loss of cellular ATP content with mitochondrial membrane depolarization and an increased formation of reactive oxygen species; all these processes were markedly prevented by the mitochondrial permeability transition pore blocker cyclosporine A, which did not affect complex I inhibition by rotenone. The nuclear morphology of rotenone-treated cells for 48 h indicated the presence of both necrosis and apoptosis. We then examined the effects of cyclosporine A on the rotenone-induced model of Parkinson's disease in Wistar rats. Cyclosporine A significantly improved the motor deficits and prevented the loss of nigral dopaminergic neurons projecting into the striatum in rotenone-treated rats. Being a marketed immuno-suppressive drug, cyclosporine A should be further evaluated for its putative neuroprotective action in Parkinson's disease.

Background and aimsRecent reports reveal incidences of spinal cord involvement in form of para-infectious or post-infectious myelitis raising potential concerns about the possibilities of SARS-CoV-2 behind the pathogenesis of spinal cord demyelination. In this study, we intend to summarise so far available pieces of evidence documenting SARS-CoV-2 mediated spinal demyelination in terms of clinical, laboratory parameters and imaging characteristics.MethodologyThis review was carried out based on the existing PRISMA (Preferred Report for Systemic Review and Meta-analyses) consensus statement. Data was collected from four databases: Pubmed/Medline, NIH Litcovid, Embase and Cochrane library and Preprint servers up till 10th September, 2020. Search strategy comprised of a range of keywords from relevant medical subject headings which includes “SARS-COV-2”, “COVID-19”, “demyelination” etc.ResultsA total of 21 cases were included from 21 case reports after screening from various databases and preprint servers. Biochemical analysis reveals that the majority of cases showed elevated CSF protein as well as lymphocytic pleocytosis. Interestingly, a majority of cases were found to be associated with long extensive transverse myelitis (LETM), and remaining cases were found to be associated with isolated patchy involvement or isolated short segment involvement or combined LETM and patchy involvement. Few cases were also found with significant co-involvement of the brain and spine based on the imaging data.ConclusionIt can be interpreted that SARS-CoV-2 may play a potential role in spinal demyelinating disorders in both para-infectious and post-infectious forms.HighlightsImaging data reveals LETM, short and patchy involvementsPara infectious myelitis precedes post-infectious manifestationAltered CSF parameters and myelitis-like symptoms at the onset of COVID-19Similar spinal cord involvements in related HCoVs infections

The cytotoxicity of dopamine on cultured cells of neural origin has been used as a tool to explore the mechanisms of dopaminergic neurodegeneration in Parkinson's disease. In the current study, we have shown that dopamine induces a dose-dependent (10-40 μM) and time-dependent (up to 96 h) loss of cell viability associated with mitochondrial dysfunction and increased intra-cellular accumulation of α-synuclein in cultured SH-SY5Y cells. Dopamine-induced mitochondrial dysfunction and the loss of cell viability under our experimental conditions could be prevented by cyclosporine, a blocker of mitochondrial permeability transition pore, as well as the antioxidant N-acetylcysteine. Interestingly, the dopamine effects on cell viability and mitochondrial functions were significantly prevented by knocking down α-synuclein expression by specific siRNA. Our results suggest that dopamine cytotoxicity is mediated by α-synuclein acting on the mitochondria and impairing its bioenergetic functions.

The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.

The COVID-19 pandemic has caused immense damage to most nations of the world, both in terms of loss of human lives, as well as, socio-economic attributes. The immunopathogenesis of the responsible pathogen, SARS-CoV-2, has been a focal point and researchers have succeeded in deciphering the multi-organ tropism of the virus along with its different routes of infection. The hallmark feature of the SARS-CoV-2 disease pathogenesis is the high rates of transmission and the susceptibility of a vulnerable group with systemic co-morbidities. Also, genetic components of the host, as well as mutant variants of the virus have further complicated the development of appropriate treatment strategies and preventive measures. The virus is aptly able to modulate the host immune system and mediate immune-dysregulation in terms of cytokine or chemokine production leading to a heightened inflammatory response. In the current review, we have summarized the present research on SARS-CoV-2 from the angles of host genetic polymorphism, genetic variants of the virus, and how these affect the high transmission, disease susceptibility, and tissue tropism in multiple organs of the human body.

Background: There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. Methods: A review of literature was performed by searching PubMed and Google Scholar for relevant articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of targeting various pathways related to this protein. Results: The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α-synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process. At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of this protein. Conclusion: Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.

Background : Spinal cord complications associated with coronavirus infectious disease of 2019 (COVID-19) are being widely reported. The purpose of this systematic review was to summarize so far available pieces of evidence documenting de novo novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) mediated spinal cord demyelinating diseases. Indeed, the spinal demyelinating disorders that have been reported in those patients who have suffered from COVID-19 rather than on the people already living with diagnosed or undiagnosed primary demyelinating disorders. Methods : We used the existing PRISMA consensus statement. Data were collected from PubMed, NIH Litcovid, EMBASE and Cochrane library databases, as well as Pre-print servers (medRxiv, bioRxiv, and pre-preints.org), until September 10, 2020, using pre-specified searching strategies. Results : The 21 selected articles were all case reports and included 11 (52%) men and 10 (48%) women. The mean age was of 46.7 ± 18.0. The neurological manifestations included weakness, sensory deficit, autonomic dysfunction and ataxia. In most cases, elevated cerebrospinal fluid protein as well as lymphocytic pleocytosis were found. SARS-CoV-2 was detected in five (24%) patients, meanwhile in 13 (62%) patients, the testing was negative. Testing was not performed in two cases and, in one, data were unavailable. Nearly half of the cases (N = 9) were associated with isolated long extensive transverse myelitis (LETM), whereas a combination of both LETM and patchy involvement was found in two. Only five patients had isolated short segment involvement and two patchy involvement. Furthermore, concomitant demyelination of both brain and spine was reported in six patients. Concerning the prognosis, most of the patients improved and the mortality rate was low (N = 2, Conclusion : Spinal cord demyelination should be added to the plethora of immune mediated neurologic complications associated with COVID-19.

The present study demonstrates the efficacies of synthetic 1,8-cineole and an 1,8-cineole-rich supercritical carbon dioxide (SC-CO2) extract of small cardamom seeds in preventing oligomerization of amyloid beta peptide (Aβ42) and inhibiting iron-dependent oxyradical production in vitro. The oligomerization of Aβ42 was monitored by thioflavin T assay and MALDI-TOF analysis of the oligomers. The iron-dependent production of oxygen free radicals was detected by fluorometric benzoate hydroxylation assay. We observed that both pure 1,8-cineole and 1,8-cineole-rich extract of small cardamom seeds at concentrations of 50 µM and 100 µM prevented the production of reactive hydroxyl radicals from a mixture of Fe2+ and ascorbate. However, the 1,8-cineole-rich extract of small cardamom seeds prevented in vitro Aβ42 oligomerization more effectively vis-a-vis the synthetic (99% pure) 1,8-cineole. Additional study on SHSY5Y cells indicated that both pure 1,8-cineole and 1,8-cineole-rich SC-CO2 extract of small cardamom seeds prevented iron-dependent cell death. Since oxidative damage, Aβ42 aggregation and loss of cell viability (iron-induced) are characteristics of onset of Alzheimer’s disease pathology, our results suggest a putative therapeutic role of 1,8-cineole-rich extract of small cardamom seeds over pure 1,8-cineole in preventing this neurodegenerative disease.

To evaluate oxidative stress and glucose-6-phosphate dehydrogenase (G6PD) status of alcoholics and discern their association, if any, with visual contrast sensitivity function.Forty male alcoholic subjects and 36 male non-alcoholic subjects with the same age and nutritional status were enrolled in this study. Serum malondialdehyde (MDA) level and glucose-6-phosphate dehydrogenase (G6PD) activity of erythrocytes were determined by spectrophotometric assay. Contrast sensitivity (CS) function of study subjects was measured using the Rabin Contrast Sensitivity Test (Precision VisionSerum MDA levels were significantly higher (p 0.0001) and erythrocyte G6PD activity was significantly lower (p = 0.0026) in alcoholic subjects compared to the controls. CS scores of both eyes were also found to be decreased significantly in alcoholic subjects (both at p 0.0001) compared to control subjects. On the other hand, CS scores of the alcoholic subjects were inversely correlated with the serum MDA level (r = -0.746, p 0.0001) and directly correlated with erythrocyte G6PD activity (r = 0.78, p 0.0001). A strong inverse correlation (r = -0.84, p 0.0001) was also observed between serum MDA level and erythrocyte G6PD activity of alcoholic subjects.Reduced G6PD activity and increased serum MDA level might be the key cause of the early visual abnormalities, such as reduced CS function of the alcoholic subjects.

Alzheimer’s disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.