Journey of Guillain Barre syndrome from the pre-pandemic era to the pandemic era: A 4-year retrospective study.

Aims: To study demographic and clinical profiles of Guillain Barre syndrome (GBS) in the pre-pandemic and coronavirus disease 2019 (COVID-19) pandemic era and to compare the GBS incidence, severity, and its outcome in the pre-pandemic and pandemic eras. Methodology: This is a 4-year retrospective study done in a tertiary care hospital in Delhi, India, between March 2018 and March 2022. Patients were divided into the pre-pandemic era and pandemic era (2 years before and 2 years after March 2020). Results: The number of patients (N) was 25 in the pandemic/vaccine era, while N = 49 in the pre-pandemic era. The mean duration of hospitalization was significantly higher (P = 0.03) during the pandemic era (10.68 ± 6.67 days) compared to the pre-pandemic era (7.59 ± 3.55 days). There was no statistical difference in age (P = 0.56), gender (P = 0.70), GBS variants (P = 0.40), clinical spectrum, antecedent infection (P = 0.91), Hughes Disability Score on admission and discharge (P = 0.93 and P = 0.52, respectively), respiratory involvement requiring a ventilator (P = 0.19), and mortality (P = 0.26) in both the eras. Conclusion: Our study showed no association of the incidence of GBS with the ongoing COVID-19 pandemic. The mean hospitalization days were significantly increased during COVID-19 in view of associated respiratory involvement. The commonly held hypothesis of the increase in GBS cases during the pandemic/vaccine era has not been observed in our study.

Exposure to an aversive odor alters Caenorhabditis elegans physiology.

Perception of external cues is important for enhancing the fitness and survival of animals. However, the role of odor perception in regulation of longevity and health is incompletely defined. Here, we show that the exposure to an aversive odor 2-nonanone reduces life span, brood size, feeding rate, and increases lipid storage in worms. These effects are restored to normal levels in mutant worms lacking functional olfactory AWB neurons, suggesting a potential role of odor perception in the regulation of animal physiology and longevity.

Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.

Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.

Dopaminergic Axons: Key Recitalists in Parkinson's Disease.

Parkinson's disease (PD) is associated with dopamine depletion in the striatum owing to the selective and progressive loss of the nigrostriatal dopaminergic neurons, which results in motor dysfunction and secondary clinical manifestations. The dopamine level in the striatum is preserved because of the innervation of the substantia nigra (SN) dopaminergic neurons into it. Therefore, protection of the SN neurons is crucial for maintaining the dopamine level in the striatum and for ensuring the desired motor coordination. Several strategies have been devised to protect the degenerating dopaminergic neurons or to restore the dopamine levels for treating PD. Most of the methods focus exclusively on preventing cell body death in the neurons. Although advances have been made in understanding the disease, the search for disease-modifying drugs is an ongoing process. The present review describes the evidence from studies involving patients with PD as well as PD models that axon terminals are highly vulnerable to exogenous and endogenous insults and degenerate at the early stage of the disease. Impairment of mitochondrial dynamics, Ca2+ homeostasis, axonal transport, and loss of plasticity of axon terminals appear before the neuronal degeneration in PD. Furthermore, distortion of synaptic morphology and reduction of postsynaptic dendritic spines are the neuropathological hallmarks of early-stage disease. Thus, the review proposes a shift in focus from discerning the mechanism of neuronal cell body loss and targeting it to an entirely different approach of preventing axonal degeneration. The review also suggests appropriate strategies to prevent the loss of synaptic terminals, which could induce regrowth of the axon and its auxiliary fibers and might offer relief from the symptomatic features of PD.

Fourteen (14) months follow up of traumatic sciatic neuritis due to intramuscular injection: a case report.

The injury caused due to the intramuscular (IM) mode of drug administration are still affecting population in rural area more than urban area. The IM injection given in any quadrant except the upper outer quadrant of buttock most commonly damages the sciatic nerve because of its course and extent in the injection prone site. The iatrogenic sciatic nerve injury because of IM injection in dorsogluteal site is a matter of concern all over the world covering the undeveloped, developing and developed countries. The iatrogenic sciatic neuritis causes severe neurological or motor deficits leading to the medico-legal consequences. An 8-year-old male child, post dorsogluteal IM injection for mild fever and cold, presented left lower limb weakness and pain in left gluteal region. The patient underwent the medical and physiotherapeutic management for 14 months. The medical management included the initial dose of steroids and ox carbamazepine along with methylcobalamine and folic acid. The physiotherapeutic intervention concentrated on the functional independency of child. The patient attended complete physiological and functional recovery by the end of 14th month concluding that sometimes waiting for lesion to resolve is better than intervention. The iatrogenic sciatic neuritis is a complication that needs attention for prevention following intramuscular drug administration technique.

Multicorrection Goldenhar syndrome (facio-auriculo-vertebral dysplasia): a rare follow-up case of 12-year-old female.

The MSX homeobox genes cause Goldenhar syndrome (GHS) or facio-auriculo-vertebral dysplasia, a rare developmental defect. Its exact etiology is still unknown. Its incidence lies between 1: 3500 and 1: 5600. In 85% of the cases, the unilateral face is affected. Typical clinical findings in a classic GHS include eye disorders, ear irregularities (with or without hearing loss), facial impairments, dental and oral ailments, cardiac syndromes, central nervous system (CNS) involvement, trachea and lung malformations, kidney and gastrointestinal defects, and skeletal alterations. This case report presents a follow-up case of Goldenhar Syndrome in a 12-year-old female, with no relevant family history, diagnosed with anotia on the left side, cyanosis, and facial asymmetry at birth. She presented with moderate growth failure, bilateral sclerosing mastoiditis and kyphoscoliosis. She underwent posterior scoliosis correction posterior instrumented fusion from D1 to D11.

Sensory perception of environmental cues as a modulator of aging and neurodegeneration: Insights from Caenorhabditis elegans.

Environmental stimuli such as temperature, food, and smell significantly influence the physiology and behavior of animals. Animals are differentially adapted to maintain their internal body functions in response to varied environmental conditions. These external cues are sensed by specialized neurons which are a part of the chemosensory and thermosensory systems. The inability to respond correctly to varied environmental conditions may result in compromised bodily functions and reduced longevity. For example, the ability to sense food is derived from the integrated action of olfactory and gustatory systems. The damage to the olfactory system will affect our decision of palatable food items which in turn can affect the response of the gustatory system, ultimately causing abnormal feeding habits. Recent studies have provided evidence that aging is regulated by sensory perception of environment. Aging is one of the most common causes of various neurodegenerative diseases and the perception of environmental cues is also found to regulate the development of neurodegenerative phenotype in several animal models. However, specific molecular signaling pathways involved in the process are not completely understood. The research conducted on one of the best-studied animal models of aging, Caenorhabditis elegans, has demonstrated multiple examples of gene-environment interaction at the neuronal level which affects life span. The findings may be useful to identify the key neuronal regulators of aging and age-related diseases in humans owing to conserved core metabolic and aging pathways from worms to humans.

Neuronal control of lipid metabolism by STR-2 G protein-coupled receptor promotes longevity in Caenorhabditis elegans.

The G protein-coupled receptor (GPCR) encoding family of genes constitutes more than 6% of genes in Caenorhabditis elegans genome. GPCRs control behavior, innate immunity, chemotaxis, and food search behavior. Here, we show that C. elegans longevity is regulated by a chemosensory GPCR STR-2, expressed in AWC and ASI amphid sensory neurons. STR-2 function is required at temperatures of 20°C and higher on standard Escherichia coli OP50 diet. Under these conditions, this neuronal receptor also controls health span parameters and lipid droplet (LD) homeostasis in the intestine. We show that STR-2 regulates expression of delta-9 desaturases, fat-5, fat-6 and fat-7, and of diacylglycerol acyltransferase dgat-2. Rescue of the STR-2 function in either AWC and ASI, or ASI sensory neurons alone, restores expression of fat-5, dgat-2 and restores LD stores and longevity. Rescue of stored fat levels of GPCR mutant animals to wild-type levels, with low concentration of glucose, rescues its lifespan phenotype. In all, we show that neuronal STR-2 GPCR facilitates control of neutral lipid levels and longevity in C. elegans.

Proteomics in Human Parkinson's Disease: Present Scenario and Future Directions.

Parkinson's disease (PD) is an age-related, threatening neurodegenerative disorder with no reliable treatment till date. Identification of specific and reliable biomarker is a major challenge for disease diagnosis and designing effective therapeutic strategy against it. PD pathology at molecular level involves abnormal expression and function of several proteins, including alpha-synuclein. These proteins affect the normal functioning of neurons through various post-translational modifications and interaction with other cellular components. The role of protein anomalies during PD pathogenesis can be better understood by the application of proteomics approach. A number of proteomic studies conducted on brain tissue, blood, and cerebrospinal fluid of PD patients have identified a wide array of protein alterations underlying disease pathogenesis. However, these studies are limited by the types of brain regions or biofluids utilized in the research. For a complete understanding of PD mechanism and discovery of reliable protein biomarkers, it is essential to analyze the proteome of different PD-associated brain regions and easily accessible biofluids such as saliva and urine. The present review summarizes the major advances in the field of PD research in humans utilizing proteomic techniques. Moreover, potential samples for proteomic analysis and limitations associated with the analyses of different types of samples have also been discussed.

Cyclosporine A and MnTMPyP Alleviate α-Synuclein Expression and Aggregation in Cypermethrin-Induced Parkinsonism.

Cypermethrin induces the mitochondrial dysfunction and oxidative damage to the nigrostriatal dopaminergic neurons leading to Parkinsonism in rats. Despite α-synuclein aggregation is reported to be critical in Parkinson's disease, its role and alliance with the mitochondrial dysfunction and oxidative damage leading to cypermethrin-induced Parkinsonism have not yet been deciphered. The present study aimed to examine the effect of cypermethrin on the expression and aggregation of α-synuclein and its subsequent connection with oxidative damage and mitochondrial dysfunction leading to the nigrostriatal dopaminergic neurodegeneration in the presence or absence of a mitochondrial membrane transition pore opening inhibitor, cyclosporine A and a superoxide dismutase/catalase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP). The expression of α-synuclein, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE)-modified proteins, mitochondrial dysfunction-dependent apoptotic proteins, nitrite content, lipid peroxidation (LPO) and number of tyrosine hydroxylase (TH)-positive neurons were estimated in the substantia nigra and dopamine content in the striatum of control and treated rats employing standard procedures. Cypermethrin augmented the expression of α-synuclein, 3-NT, 4-HNE-modified proteins, caspase-3, mitochondrial Bax and cytosolic cytochrome-c along with nitrite and LPO and reduced the expression of cytosolic Bax, mitochondrial cytochrome-c, dopamine and number of TH-positive neurons. Cyclosporine A or MnTMPyP alleviated the expression and aggregation of α-synuclein along with indicators of the mitochondrial dysfunction, oxidative damage and dopaminergic neurodegeneration. The results demonstrate that cypermethrin induces α-synuclein expression and aggregation while cyclosporine A or MnTMPyP rescues from α-synuclein over-expression and aggregation along with the mitochondrial dysfunction and oxidative damage leading to Parkinsonism in rats.

Aberrant autophagy and parkinsonism: does correction rescue from disease progression?

Information generated from animal models, genome sequencing, and high-throughput technologies provide valuable sequence of events to understand the Parkinson's disease (PD) pathogenesis. A dynamic equilibrium between biosynthesis and biodegradation of sub-cellular components by ubiquitin proteasome system and autophagy is found to be responsible for sustaining the homeostasis of tyrosine hydroxylase-positive neurons. Autophagy degrades and eliminates α-synuclein, Parkin, ubiquitin, etc., proteins along with damaged cellular components to maintain the homeostasis of the nigrostriatal dopaminergic neurons. Aberrant type II apoptosis is widely implicated in dopaminergic neurodegeneration leading to PD. The current article reviews the elementary role of autophagy in the degradation and elimination of superfluous and aggregated proteins and impaired mitochondria. The article also recapitulates the information, which implicated the role of aberrant autophagy in toxin-induced Parkinsonism. Moreover, the review sheds light on whether or not targeting the defective autophagy could reinstate the normal functioning of dopaminergic neurons, which could ultimately rescue from PD pathogenesis.

Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease.

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.

Rodent models and contemporary molecular techniques: notable feats yet incomplete explanations of Parkinson's disease pathogenesis.

Rodent models and molecular tools, mainly omics and RNA interference, have been rigorously used to decode the intangible etiology and pathogenesis of Parkinson's disease (PD). Although convention of contemporary molecular techniques and multiple rodent models paved imperative leads in deciphering the role of putative causative factors and sequential events leading to PD, complete and clear-cut mechanisms of pathogenesis are still hard to pin down. The current article reviews the implications and pros and cons of rodent models and molecular tools in understanding the molecular and cellular bases of PD pathogenesis based on the existing literature. Probable rationales for short of comprehensive leads and future possibilities in spite of the extensive applications of molecular tools and rodent models have also been discussed.

Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse.

A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30 mg/kg), twice a week, for 9 weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation.

Tiny non-coding RNAs in Parkinson's disease: implications, expectations and hypes.

Parkinson's disease (PD) is the second most prevalent, progressive and aging related neurodegenerative disorder, characterized by the irreversible and selective degeneration of the nigrostriatal dopaminergic neurons. The early diagnosis, molecular explanation and permanent cure of this devastating and baffling disease have not yet been completely deciphered. Tiny non-coding RNAs, which consist of small or short interfering RNA (siRNA) and micro RNA (miRNA), intervene with and silence the expression of the specific genes through the evolutionary conserved process of RNA interference and act as post-transcriptional regulators. The differential expression patterns of miRNAs operate as key watchdogs and facilitate the identification of the potential therapeutic targets; however, miRNA modifiers aid in designing the strategies to encounter PD. Similarly, siRNA-mediated gene silencing paves the way to understand the function of the specific genes in PD pathogenesis by knocking down their expression. Applications of siRNAs and contributions of the potential miRNAs in investigating the etiology and molecular mechanisms of PD as well as in therapeutic interventions have been discussed in this article. The review also highlights the achievements, expectations and hypes associated with these tiny non-coding RNAs in PD.

Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: microglial activation-dependent and -independent regulations.

The study aimed to identify the differentially expressed nigrostriatal proteins in cypermethrin-induced neurodegeneration and to investigate the role of microglial activation therein. Proteomic approaches were used to identify the differentially expressed proteins. Microglial activation, tyrosine hydroxylase immunoreactivity (TH-IR), dopamine content, and neurobehavioral changes were measured according to the standard procedures. The expressions of α-internexin intermediate filament (α-IIF), ATP synthase D chain (ATP-SD), heat shock protein (Hsp)-70, truncated connexin-47, Hsp-60, mitogen-activated protein kinase-activated kinase-5, nicotinamide adenine dinucleotide dehydrogenase 24k chain precursor, platelet-activating factor acetyl hydrolase 1b-α2 (PAF-AH 1b-α2), and synaptosomal-associated protein-25 (SNAP-25) were altered in the substantia nigra and nicotinamide adenine dinucleotide- specific isocitrate dehydrogenase, phosphatidylethanolamine-binding protein-1, prohibitin, protein disulfide isomerase-endoplasmic reticulum 60 protease, stathmin, and ubiquitin-conjugating enzyme in the striatum along with motor impairment, decreased dopamine and TH-IR, and increased microglial activation after cypermethrin exposure. Minocycline restored α-IIF, ATP-SD chain, truncated connexin-47, Hsp-60, PAF-AH 1b-α2, stathmin and SNAP-25 expressions, motor impairment, dopamine, TH-IR, and microglial activation. The results suggest that cypermethrin produces microglial activation-dependent and -independent changes in the expression patterns of the nigrostriatal proteins leading to dopaminergic neurodegeneration.