The potential roles of deubiquitinating enzymes in brain diseases.

Cumulative multiple early life hits- a potent threat leading to neurological disorders.

BACKGROUND Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). METHODS Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology. RESULTS LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. CONCLUSION IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

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Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep.

In recent years, clinical studies have shown strong epidemiological evidence of an increased risk of developing neuropsychiatric disorders after childhood exposure to streptococcal infection, including the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). New preclinical studies on group A streptococcus (GAS) exposure investigate how to disentangle the influences of immune activation to induce long-term neurobehavioral effects associated with neuropsychiatric disorders such as obsessive-compulsive disorder, schizophrenia or autism. The present systematic review collects neurobehavioral evidence regarding the use of GAS exposure in animal models to study the vulnerability to different neuropsychiatric disorders, improving our understanding of its possible causes and consequences, and compares its contribution with other preclinical models of immune activation in a variety of paradigms. Specifically, we reviewed the effects of postnatal GAS exposure, in comparison with post- and prenatal exposure to Lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly I:C), on the long-term effects concerning psychomotor, cognition and socioemotional outcomes in rodents. GAS exposure in animal models has revealed different behavioral alterations such as reduced locomotion and motor coordination, a deficit in sensorimotor gating, learning, working memory, altered social behavior, and increased anxiety and stereotyped behavior. Most of the results found are in accordance with other immune activation models -LPS and Poly I:C-, with some discrepancies. The systematic review of the literature supports the preclinical model of GAS exposure as a valid model for studying the neurobehavioral consequences of streptococcal infections. Future studies on streptococcal infection could contribute increasing our knowledge on preventive actions or treatments for neuropsychiatric disorders.

Neuropsychiatric consequences of childhood group A streptococcal infection: A systematic review of preclinical models

Delay of gCJD aggravation in sick TgMHu2ME199K mice by combining NPC transplantation and Nano-PSO administration.

Background Neonatal bacterial infections have been reported to cause white matter loss, although studies concerning the influence of infection on the expression of myelin and aging are still in their emerging state. Purpose The present study aimed to investigate the effects of perinatal lipopolysaccharide (LPS) exposure on the myelination at different age points using histochemical and immunocytochemical techniques and the relative motor coordination. Methods A rat bacterial infection model was established by exposing the neonatal rats with LPS (0.3 mg/kg body weight, i.p., on postnatal day (PND) 3 followed by a booster at PND 5) and its impact was studied on the myelination and motor coordination in young, adult, and senile rats. Results The results obtained suggest that the administration of LPS induces demyelination, predominantly in cortex and corpus callosum. Low expression level of myelin oligodendrocyte glycoprotein (MOG) was observed at all time points, with prominence at 12, 18, and 24 months of age. In addition, reduced staining with luxol fast blue stain was also recorded in the experimentals. With the increasing demyelination and declining motor ability, LPS exposure also seemed to accelerate normal aging symptoms. Conclusion There is a direct correlation of myelin damage and poor motor coordination with age. This would provide a better incite to understand inflammation-associated demyelinating changes in age-associated neurodegenerative disorders. Since, no long-term studies on behavioral impairments caused by LPS-induced demyelination in the central nervous system has been reported so far, this work would help in the better understanding of the long-term pathological effects of bacterial-induced demyelination.

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Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain.

Neurodegenerative diseases are a leading apprehension in underdeveloped and developed countries. The advancement of medical science is synonymous with an increase in life expectancy, which results in an aging population. Neurodegenerative diseases in the older population are on the rise globally. This review sums up the novel therapeutic approaches for Alzheimer's and Parkinson's disease. Although most neurodegenerative diseases occur due to the accumulation of misfolded proteins, the mechanisms are not completely understood. Currently, only prophylactic therapies are available and none are preventive in nature. The World Health Organisation estimates that neurodegenerative diseases that cause cognitive and motor impairments will be the second most ubiquitous cause of death in the next decade, hence the need for novel therapeutic targets for these diseases is demanded. In Alzheimer's, β-amyloid and tau proteinopathies are prevalent, whereas a prion-like increase of α- synuclein is the characteristic trait of Parkinson's disease.

Novel Therapeutics for the Treatment of Alzheimer's and Parkinson's Disease.

Breast cancer (BC) stands at the first position among all forms of malignancies found in women globally. The available therapeutic approaches for breast cancer includes chemotherapy, radiation therapy, hormonal therapy and finally surgery. Despite the conventional therapies, in recent years the advance immunology based therapeutics emerge a potential in breast cancer treatment, including immune checkpoint blockades, vaccines and in combination with other treatment strategies. Although, commonly used treatments like trastuzumab/pertuzumab for human epidermal growth factor receptor 2 (Her2) positive and hormone therapy for estrogen receptor (ER) positive and/or progesterone receptor (PR) positive BC are specific but triple negative breast cancer (TNBC) cases remain a great challenge for treatment measures. Immune checkpoint inhibitors (anti-PD-1/ anti-CTLA-4) and anti-cancer vaccines (NeuVax, Muc-1, AVX901, INO-1400 and CEA), either alone or in combination with other therapies have created new paradigm in therapeutic world. In this review, we highlighted the current immunotherapeutic aspects and their ongoing trials towards the better treatment regimen for BC.

Immunotherapy for the Breast Cancer treatment: Current Evidence and Therapeutic Options.

Impaired adult hippocampal neurogenesis is a prominent feature of neurodegenerative disorders. The extent of neural stem cell (NSCs) generation in adult brain is highly adaptive and depends on both inflammatory signalling and glial cells. In this study, through immunohistochemical co-labelling of nestin and glial fibrillary acidic protein (GFAP), the authors have demonstrated an enhanced stem astrocyte density in subgranular zone of adult and ageing rats following neonatal lipopolysaccharide (LPS) exposure, which could be attributed as a regenerative attempt evoked to overcome the effects of bacterial infection. However, a second hit of LPS at 12 months of age might have killed the progenitors because of the persistent glial activation leading to a decline in stem astrocyte population. The enhanced density of NSCs is attributed to the activation of the toll-like receptor-4 (TLR-4) by LPS on their surface that in turn influences their proliferative potential. The information generated may be useful for therapeutically modulating the pathway in a way so that the TLR-4 activation following bacterial infection may be checked at a level when it triggers the activation of the innate immune response. Thus, the enhanced number of NSCs can generate a viable number of neurons that will mature and integrate in the hippocampal circuitry to compensate the loss due to bacterial infection.

Kavita Singh

Papers

Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain.

Novel Therapeutics for the Treatment of Alzheimer's and Parkinson's Disease.

Immunotherapy for the Breast Cancer treatment: Current Evidence and Therapeutic Options.

Enhanced Adult Neural Stem Cell Population Following Bacterial Infection during Early Postnatal Life