S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

INTRODUCTION: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aß)-40, Aß42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aß levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Assessment of Neurologic Safety Profile of Immune Checkpoint Inhibitors: Evaluation of Adverse Drug Reaction Reports.

BACKGROUND: Immune checkpoint inhibitors (ICIs) used in immunotherapy have revolutionized cancer management. However, ICI therapy can come with serious neurologic risks. OBJECTIVE: The objective of our study is to analyze the occurrence of neurologic events with ICIs. METHODS: We referred to EudraVigilance (EV) and VigiAccess to evaluate the frequency of individual case safety reports (ICSRs), including neurologic events with ICIs. Data was gathered for a period from the date of ICI's marketing authorization till 30 January 2023. The computational assessment was conducted with the help of reporting odds ratio (ROR) and its 95% confidence interval (CI). RESULTS: Overall, 8181 ICSRs in EV and 15905 ICSRs from VigiAccess were retrieved for neurologic events, with at least one ICI as the suspected drug. The majority of the ICSRs were reported for nivolumab, pembrolizumab, and ipilimumab, whereas frequently reported events were neuropathy peripheral, myasthenia gravis, seizure, Guillain-Barre syndrome, paraesthesia, syncope, encephalopathy, somnolence. Under EV, 92% of ICSRs were reported as serious, 10% included fatal outcomes, and nearly 61% cited patient recovery. Atezolizumab (ROR 1.64, 95% CI 1.75- 1.52), cemiplimab (ROR 1.61, 95% CI 1.98-1.3), and nivolumab (ROR 1.38, 95% CI 1.44-1.31) had a considerable increase in the frequency of ICSR reporting. Cerebrovascular accident, posterior reversible encephalopathy syndrome, tremor, and somnolence were identified as potential signals. CONCLUSION: ICIs were significantly associated with neurologic risks, which cannot be generalized. A considerable increase in ICSR reporting frequency was observed with atezolizumab, cemiplimab, and nivolumab, while avelumab, pembrolizumab, durvalumab, and cemiplimab were linked with four potential signals. These findings suggest the consideration of a revision of the neurologic safety profile of ICIs. Furthermore, the necessity for additional ad-hoc research is emphasized.

Effect of Human Infant Gut Microbiota on Mouse Behavior, Dendritic Complexity, and Myelination.

The mammalian gut microbiome influences numerous developmental processes. In human infants it has been linked with cognition, social skills, hormonal responses to stress, and brain connectivity. Yet, these associations are not necessarily causal. The present study tested whether two microbial stool communities, common in human infants, affected behavior, myelination, dendritic morphology, and spine density when used to colonize mouse models. Humanized animals were more like specific-pathogen free mice than germ-free mice for most phenotypes, although in males, both humanized groups were less social. Both humanized groups had thinner myelin sheaths in the hippocampus, than did germ-free animals. Humanized animals were similar to each other except for dendritic morphology and spine density where one group had greater dendritic length in the prefrontal cortex, greater dendritic volume in the nucleus accumbens, and greater spine density in both regions, compared to the other. Results add to a body of literature suggesting the gut microbiome impacts brain development. Teaser: Fecal transplants from human infants with highly abundant Bifidobacterium , an important inhabitant of the intestinal tract of breastfed newborns, may promote brain connectivity in mice.

Cardiac safety profile of type II kinase inhibitors: Analysis of post-marketing reports from databases of European Medicine Agency & World Health Organization.

BACKGROUND: Targeted therapy with type II kinase inhibitors (KIs) is one of the preferred choices in cancer treatment. However, type II KI therapy can be associated to serious cardiac risks. OBJECTIVES: This study aimed to assess the occurrence of cardiac events reported with type II KIs in Eudravigilance (EV) and VigiAccess databases. METHODS: To evaluate reporting frequency of individual case safety reports (ICSRs) related to cardiac events, we referred EV and VigiAccess databases. The data was retrieved for the period from date of marketing authorization of respective type II KI till 30 July 2022. Computational analysis was conducted with data from EV and VigiAccess using reporting odds ratio (ROR) along with its 95% confidence interval (CI) under Microsoft excel. RESULTS: In total, 14429 ICSRs in EV and 11522 ICSRs from VigiAccess were retrieved concerning cardiac events with at least one type II KI as the suspected drug. In both databases, most of the ICSRs were reported for Imatinib, Nilotinib, and Sunitinib, while most reported cardiac events were myocardial infarction/acute myocardial infarction, cardiac failure/congestive heart failure and atrial fibrillation. As per EV, 98.8% ICSRs with cardiac ADRs were assessed as serious and of which, 17.4% ICSRs were associated with fatal outcomes and approximately 47% included patient's recovery as a favorable outcome. Nilotinib (ROR 2.87, 95% CI 3.01-2.74) and Nintedanib (ROR 2.17, 95% CI 2.3-2.04) were associated with a significant increase in reporting frequency of ICSRs related to cardiac events. CONCLUSIONS: Type II KI related cardiac events were serious and associated with unfavorable outcomes. A significant increase in ICSRs reporting frequency was observed with Nilotinib and Nintedanib. These results insist for a consideration of revision of cardiac safety profile of Nilotinib and Nintedanib, specifically for risks of myocardial infarction and atrial fibrillation. Additionally, the need for other ad-hoc studies is indicated.

S-nitrosoglutathione modulates HDAC2 and BDNF levels in the brain and improves cognitive deficits in experimental model of Alzheimer's disease in rats.

AIM: Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer's disease (sAD). METHODS: AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3 mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-ß, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. RESULTS: The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50 µg/kg) and, to a lesser extent, L-arginine (100 mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid ß, BDNF and HDAC2 levels in hippocampus. CONCLUSIONS: It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition.

SARS-CoV-2 (COVID-19) as a possible risk factor for neurodevelopmental disorders.

Pregnant women constitute one of the most vulnerable populations to be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019. SARS-CoV-2 infection during pregnancy could negatively impact fetal brain development via multiple mechanisms. Accumulating evidence indicates that mother to fetus transmission of SARS-CoV-2 does occur, albeit rarely. When it does occur, there is a potential for neuroinvasion via immune cells, retrograde axonal transport, and olfactory bulb and lymphatic pathways. In the absence of maternal to fetal transmission, there is still the potential for negative neurodevelopmental outcomes as a consequence of disrupted placental development and function leading to preeclampsia, preterm birth, and intrauterine growth restriction. In addition, maternal immune activation may lead to hypomyelination, microglial activation, white matter damage, and reduced neurogenesis in the developing fetus. Moreover, maternal immune activation can disrupt the maternal or fetal hypothalamic-pituitary-adrenal (HPA) axis leading to altered neurodevelopment. Finally, pro-inflammatory cytokines can potentially alter epigenetic processes within the developing brain. In this review, we address each of these potential mechanisms. We propose that SARS-CoV-2 could lead to neurodevelopmental disorders in a subset of pregnant women and that long-term studies are warranted.

Alzheimer's Disease: A Contextual Link with Nitric Oxide Synthase.

Nitric oxide (NO) is a gasotransmitter with pleiotropic effects which has made a great impact on biology and medicine. A multidimensional neuromodulatory role of NO has been shown in the brain with specific reference to neurodegenerative disorders like Alzheimer's disease (AD) and cognitive dysfunction. It has been found that NO/cGMP signalling pathway has an important role in learning and memory. Initially, it was considered that indirectly NO exerted neurotoxicity in AD via glutamatergic excitotoxicity. However, considering the early development of cognitive functions involved in the learning memory process including long term potentiation and synaptic plasticity, NO has a crucial role. Increasing evidence uncovered the above facts that isoforms of NOS viz endothelial NO synthase (eNOS), neuronal NO synthase (nNOS) and inducible NO synthase (iNOS) having a variable expression in AD are mainly responsible for learning and memory activities. In this review, we focus on the role of NOS isoforms in AD parallel to NO. Further, this review provides convergent evidence that NO could provide a therapeutic avenue in AD via modulation of the relevant NOS expression.

Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer's disease in rats.

The present study evaluated the effects of s-nitrosoglutathione (GSNO), a nitrosothiol and sustained NO releaser, on experimental model of sporadic Alzheimer`s disease (sAD) in rats. Levels of Aß40, Aß42 and BDNF were assessed in brain hippocampal homogenates for correlative purposes. Intracerebroventricular-Streptozotocin (icv-STZ) induced increased escape latencies (acquisition) and reduced time in target quadrant (probe trial) in Morris Water Maze (MWM) test at 3 months post icv-STZ administration. These behavioural changes were associated with increased Aß depositions and lowered BDNF levels in brain hippocampal homogenates. Pre-treatment with GSNO (50 µg/kg/day), reduced the icv-STZ induced cognitive deficits in acquisition and probe trials in the MWM. The icv-STZ induced elevations in Aß40 and Aß42 and reduced levels of BDNF in hippocampal homogenates were also attenuated after GSNO treatment in these rats. The NO-precursor, l-arginine (100 mg/kg) induced similar effects on behavioural and biochemical parameters tested but was marginally less consistent as compared to those seen with GSNO. The results suggest that GSNO ameliorates the cognitive deficits and associated brain biochemical changes in this experimental model of sporadic AD, and NO-BDNF interactions could play crucial role in these effects.

Recent studies on cellular and molecular mechanisms in Alzheimer's disease: focus on epigenetic factors and histone deacetylase.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes: ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, MS4A6A, MS4A4E, and PICALM, which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment.

Antihypertensive effect of allicin in dexamethasone-induced hypertensive rats.

BACKGROUND: Glucocorticoid is among the most commonly prescribed medicine. Unfortunately, Excess glucocorticoid level leads hypertension in 80-90% patients. Garlic (Allium sativum) has been used since ancient times and even nowadays as a part of popular medicine for various ailments and physiological disorders. Hence this study was undertaken to investigate the antihypertensive activity of allicin in dexamethasone induced hypertension in wistar rats. METHODS: The animals were randomly divided into four groups comprising of six rats per group. Hypertension was induced by subcutaneous injection of dexamethasone (10 µg/rat/day) in hypertensive rats. Two hypertensive group animals were treated with nicorandil (6 mg/kg/day, po) and allicin (8 mg/kg/day, po) respectively for 8 weeks. While systolic blood pressure (SBP) was measured by the tail-cuff method weekly up to 8 weeks. RESULTS: Dexamethasone treatment resulted in significant increase in SBP while allicin treatment significantly decreases the SBP. Thus, this study confirmed that allicin treatment for 8 weeks partially reverse dexamethasone induced hypertension in rats. Allicin treatment also attenuated dexamethasone-induced anorexia and loss of total body weight. CONCLUSION: This result suggests antihypertensive effects of allicin in dexamethasone induced hypertension. However, further studies are needed to explore the detailed mechanism of antihypertensive effect of allicin.

Allicin, a SUR2 opener: possible mechanism for the treatment of diabetic hypertension in rats

The garlic (Allium sativum L., Amaryllidaceae) has been popularly used in the treatment of diabetes and cardiac complications. In the present work, we have studied the possible mechanisms, sulfonylurea receptor (SUR) selectivity of allicin in diabetic hypertensive rats. Diabetic hypertension was induced by intraperitoneal injection of streptozotocin (50 mg/kg) followed by daily administration of dexamethasone (10 µg/kg, s.c.). Different parameters, blood pressure and blood glucose levels were studied in the rats weekly up to eight weeks. Allicin (8 mg/kg, p.o.) shows potent antidiabetic (*p<0.001) as well as antihypertensive effect (**p<0.001, *p<0.01). It may act as a vasodilator by hyperpolarizing the membrane of normal vascular smooth muscle cells. The hyperpolarization in vascular smooth muscle occurs due to K+ channel opener activity. Antihypertensive effect of allicin is inhibited by glibenclamide, nonselective SUR blocker while combination of allicin with nateglinide, selective SUR1 blocker exerted synergistic antihypertensive effect. The results indicates that allicin is effective in the treatment of diabetic hypertension; through a mechanism that might involve selective opening of SUR2.