Standardized Extract of Bacopa monniera

The aim of the present study is to investigate the effect of standardized extract of Bacopa monnieri (memory enhancer) and Melatonin (an antioxidant) on nuclear factor erythroid 2 related factor 2 (Nrf2) pathway in Okadaic acid induced memory impaired rats. OKA (200 ng) was administered intracerebroventricularly (ICV) to induce memory impairment in rats. Bacopa monnieri (BM-40 and 80 mg/kg) and Melatonin (20 mg/kg) were administered 1 hr before OKA injection and continued daily up to day 13. Memory functions were assessed by Morris water maze test on days 13–15. Rats were sacrificed for biochemical estimations of oxidative stress, neuroinflammation, apoptosis, and molecular studies of Nrf2, HO1, and GCLC expressions in cerebral cortex and hippocampus brain regions. OKA caused a significant memory deficit with oxidative stress, neuroinflammation, and neuronal loss which was concomitant with attenuated expression of Nrf2, HO1, and GCLC. Treatment with BM and Melatonin significantly improved memory dysfunction in OKA rats as shown by decreased latency time and path length. The treatments also restored Nrf2, HO1, and GCLC expressions and decreased oxidative stress, neuroinflammation, and neuronal loss. Thus strengthening the endogenous defense through Nrf2 modulation plays a key role in the protective effect of BM and Melatonin in OKA induced memory impairment in rats

Blockade of \u3b14 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-beta (A beta) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1(+) vessels in 3xTg-AD transgenic mice, which develop both A beta and tau pathologies. The counter-ligand of VCAM-1-alpha 4 beta 1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4(+) T cells and was also expressed by a significant proportion of blood CD8(+) T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that alpha 4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block alpha 4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, A beta load and tau hyperphosphorylation. Our results demonstrate that alpha 4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of alpha 4 integrins may offer a new therapeutic strategy in AD

Molecular interaction of human acetylcholinesterase with trans-tephrostachin and derivatives for Alzheimer's disease

Alzheimer's disease (AD), a neurodegenerative disorder affects more than 35 million people globally. Acetylcholinesterase suppression is the common approach to enhance the well-being of AD patients by increasing the duration of acetylcholine in the cholinergic synapses. Generally, herbal secondary metabolites are reported to be a major resource for acetylcholinesterase inhibitors (AChEIs). Trans-tephrostachin was reported from Tephrosia purpurea for AChE inhibition. Here, we report on the design, synthesis, and assessment of human acetylcholinesterase inhibitory activity from trans-tephrostachin derivatives or analogs as anti-AD agents. The five newly synthesized compounds 4a. 4b, 4c, 4d and 4e displayed potent inhibitory activities with IC50 values of 35.0, 35.6, 10.6, 10.3, and 28.1 μM respectively. AChE enzyme kinetic study was performed for the five derived compounds using the Ellman's method. The Lineweaver-Burk and the secondary plots revealed the mixed inhibition for 4a, 4c and 4d whereas 4b and 4e demonstrated competitive inhibition. Molecular docking and molecular dynamics simulations showed the derivatives or analogs of trans-tephrostachin attained a high binding affinity and efficacy than the standard drug. In conclusion, trans-tephrostachin and its derivative compounds could become effective agents for further drug development to treat AD.Published versio

Systemic lupus erythematosus and myasthenia gravis: A rare association

Systemic lupus erythematosus (SLE) and myasthenia gravis (MG) are two autoimmune diseases that have a higher incidence in young females, relapsing–remitting course, and positive antinuclear antibodies. SLE and MG are two different clinical syndromes, which can coexist or precede each other; however, their occurrence in the same patient is rare. We report a 38-year-old female with biopsy-proven lupus nephritis on steroids and cyclophosphamide, later developed MG. Nerve conduction studies showed the decremental response of 15%–25% over facial muscles with no decremental response over limb muscles. Although antianticholinesterase receptor (AchR) antibodies were negative, she was treated with oral pyridostigmine 60 mg twice daily and clinical improvement of ocular symptoms was seen within 48 h. At present, she is on oral prednisolone and mycophenolate mofetil with follow-up creatinine of 1.4 mg/dl and no neurological symptoms

Control of contextual memory through interneuronal α5-GABAA receptors

γ-Aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and are strongly implicated in control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that mice in which α5-GABAARs have been eliminated from pyramidal neurons (α5-pyr-KO) continue to form strong spatial engrams and that they remain as sensitive as their pseudo-wild-type (p-WT) littermates to etomidate-induced suppression of place cells and spatial engrams. By contrast, mice with selective knockout in interneurons (α5-i-KO) no longer exhibit etomidate-induced suppression of place cells. In addition, the strength of spatial engrams is lower in α5-i-KO mice than p-WT littermates under control conditions. Consistent with the established role of the hippocampus in contextual fear conditioning, α5-i-KO mice resisted etomidate's suppression of freezing to context, but so too did α5-pyr-KO mice, supporting a role for extra-hippocampal regions in the development of contextual fear memory. Overall, our results indicate that interneuronal α5-GABAARs serve a physiological role in promoting spatial learning and that they mediate suppression of hippocampus-dependent contextual memory by etomidate

Outcomes of ST Segment Elevation Myocardial Infarction without Standard Modifiable Cardiovascular Risk Factors – Newer Insights from a Prospective Registry in India

Objectives: Patients with ST elevation myocardial infarction (STEMI) without standard modifiable cardiovascular risk factors (SMuRFs; dyslipidaemia, hypertension, diabetes mellitus and smoking) are reported to have a worse clinical outcome compared to those with SMuRFs. However, robust prospective data and low-and middle-income country perspective are lacking. We aimed to study the patients with first STEMI and assess the influence of SMuRFs on clinical outcomes by comparing the patients with and without SMuRFs. Methods: We included all consecutive STEMI patients without prior coronary artery disease enrolled in the Madras Medical College STEMI Registry from September 2018 to October 2019. We collected baseline clinical characteristics, revascularisation strategies and clinical outcome. We analysed suboptimal self-reported sleep duration as a 5th extended SMuRF (eSMuRF). Primary outcome was in-hospital mortality. Secondary outcomes included in-hospital complications and one-year all-cause mortality. Results: Among 2,379 patients, 605 patients (25.4%) were SMuRF-less. More women were SMuRF-less than men (27.1% vs 22.1%; P = 0.012). SMuRF-less patients were older (57.44 ± 13.95 vs 55.68 ± 11.74; P < 0.001), more often former tobacco users (10.4% vs 5.0%; P < 0.001), with more anterior wall MI (62.6% vs 52.1%; P = 0.032). The primary outcome [in-hospital mortality (10.7% vs 11.3%; P = 0.72)] and secondary outcomes [in-hospital complications (29.1% vs 31.7%; P = 0.23) and one-year all-cause mortality (22.3% vs 22.7%; P = 0.85)] were similar in both groups. Addition of suboptimal self-reported sleep duration as a 5th eSMuRF yielded similar results. Conclusions: 25% of first STEMI patients were SMuRF-less. Clinical outcomes of patients without SMuRFs were similar to those with SMuRFs. Suboptimal sleep duration did not account for the risk associated with the SMuRF-less status