Alternatively activated microglia and macrophages in the central nervous system.

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.

/pdf/neural-stem-cell-derived-small-extracellular-vesicles-5avb0p8682.pdf

Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer’s disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism. Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-κB p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-κB p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine. Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and NF-κB p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-κB p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-κB p65 levels as well as expression of pro-inflammatory cytokines (IL-1β, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line. These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.

/pdf/galantamine-improves-cognition-hippocampal-inflammation-and-3ooldsrwlq.pdf

Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice

Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration.

/pdf/pathophysiological-role-of-neuroinflammation-in-4k5re3c9pu.pdf

Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders.

Rationale Alcoholism is a primary, chronic relapsing disease of brain reward, motivation, memory, and related circuitry. It is characterized by an individual’s continued drinking despite negative consequences related to alcohol use, which is exemplified by alcohol use leading to clinically significant impairment or distress. Chronic alcohol consumption increases the expression of innate immune signaling molecules (ISMs) in the brain that alter cognitive processes and promote alcohol drinking. Objectives Unraveling the mechanisms of alcohol-induced neuroimmune geneinduction iscomplicated bypositiveloops of multiple cytokines and other signaling molecules that converge on nuclear factor kappa-light-chain-enhancer of activated B cells and activator protein-1 leading to induction of additional neuroimmune signaling molecules that amplify and expand the expression of ISMs. Results Studies from our laboratory employing reverse transcription polymerase chain reaction (RT-PCR) to assess mRNA, immunohistochemistry and Western blot analysis to assess protein expression, and others suggest that ethanol increases brain neuroimmune gene and protein expression through two distinct mechanisms involving (1) systemic induction of innate immune molecules that are transported from blood to the brain and (2) the direct release of high-mobility group box 1 (HMGB1) from neurons in the brain. Released HMGB1 signals through multiple receptors, particularly Tolllike receptor (TLR) 4, that potentiate cytokine receptor responses leading to a hyperexcitable state that disrupts neuronal networks and increases excitotoxic neuronal death. Innate immune gene activation in brain is persistent, consistent with the chronic relapsing disease that is alcoholism. Expression of HMGB1, TLRs, and other ISMs is increased several-fold in the human orbital frontal cortex, and expression of these molecules is highly correlated with each other as well as lifetime alcohol consumption and age of drinking onset. Conclusions The persistent and cumulative nature of alcohol on HMGB1 and TLR gene induction support their involvement in alcohol-induced long-term changes in brain function and neurodegeneration.

https://link.springer.com/content/pdf/10.1007%2Fs00213-015-3906-1.pdf

Mechanisms of neuroimmune gene induction in alcoholism

Neuroinflammation is a common feature of acute neurological conditions such as stroke and spinal cord injury, as well as neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Previous studies have demonstrated that acute neuroinflammation can adversely affect the survival of neural precursor cells (NPCs) and thereby limit the capacity for regeneration and repair. However, the mechanisms by which neuroinflammatory processes induce NPC death remain unclear. Microglia are key mediators of neuroinflammation and when activated to induce a pro-inflammatory state produce a number of factors that could affect NPC survival. Importantly, in the present study we demonstrate that tumor necrosis factor α (TNFα) produced by lipopolysaccharide-activated microglia is necessary and sufficient to trigger apoptosis in mouse NPCs in vitro. Furthermore, we demonstrate that microglia-derived TNFα induces NPC apoptosis via a mitochondrial pathway regulated by the Bcl-2 family protein Bax. BH3-only proteins are known to play a key role in regulating Bax activation and we demonstrate that microglia-derived TNFα induces the expression of the BH3-only family member Puma in NPCs via an NF-κB-dependent mechanism. Specifically, we show that NF-κB is activated in NPCs treated with conditioned media from activated microglia and that Puma induction and NPC apoptosis is blocked by the NF-κB inhibitor BAY-117082. Importantly, we have determined that NPC apoptosis induced by activated microglia-derived TNFα is attenuated in Puma-deficient NPCs, indicating that Puma induction is required for NPC death. Consistent with this, we demonstrate that Puma-deficient NPCs exhibit an ∼13-fold increase in survival as compared with wild-type NPCs following transplantation into the inflammatory environment of the injured spinal cord in vivo. In summary, we have identified a key signaling pathway that regulates neuroinflammation induced apoptosis in NPCs in vitro and in vivo that could be targeted to promote regeneration and repair in diverse neurological conditions.

Microglia-derived TNFα induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma.

Abstract Background Poor sperm quality (male infertility) is present in 50% of couples requiring assisted reproductive technologies (ART). Few couples worldwide have access to ART, and there are currently no available drugs to improve sperm function. Obesity is a major cause of male infertility. Semen reactive oxygen species (ROS), is a recently identified mechanism for sperm DNA damage resulting in reduced fertilisation and pregnancy outcomes. Semen levels of ROS are positively correlated with body mass index. However, the acute energy restriction following bariatric surgery may paradoxically reduce sperm function, making it an unsuitable treatment for male infertility. No previous randomised controlled study has been performed investigating the effects of weight loss on sperm function and semen ROS in men with obesity and infertility. We hypothesized that milder weight loss through energy restriction could be a novel treatment to reduce semen ROS and improve sperm function in men with obesity and oligospermia. Objective Determine effects of a formula low energy diet (LED) on semen parameters and ROS in men with obesity and oligospermia. Methods Thirty-six men with obesity and oligospermia participated in a 16-week randomised, controlled study. After 2-weeks of baseline observation, all men were randomised to either LED (∼800kcal/day) or a control intervention of generalised healthy eating advice lasting 16-weeks; WHO semen analysis, semen ROS, metabolic parameters and reproductive hormones were monitored throughout the study. Semen ROS was measured in relative light years/sec/million sperm (RLU/s/mill) using an in-house, validated chemiluminescent luminol-based assay. Results At baseline, men with obesity and oligospermia had significantly elevated semen ROS levels when compared with the reference range generated from healthy men with normal BMI (median (inter-quartile range) ROS in RLU/s/mill: <3.8, healthy men; 60.3(113.1), control at baseline; 82.1(100.6) LED). Participants on the LED lost 9-fold more weight compared with control intervention (weight ± SD in kg: -1.5±4.3, control; -14.3±4.5, LED, p<0.0001). After 16 weeks, median semen ROS was reduced 12-fold greater in the LED versus control group (change in ROS vs. baseline in RLU/s/mill: -0.2(61.9), control; -6.0(137.5), LED; p<0.05). Total and progressive motility, and total motile count increased in the LED group versus the control intervention, but these changes were non-significant. Conclusions This is the first randomised controlled study investigating effects of dietary weight loss on spermatogenesis in men with obesity and oligospermia. Our study provides proof-of-concept, and that weight loss could be used therapeutically in men with obesity and infertility, to reduce seminal ROS which is associated with increased sperm DNA damage. These data have important potential implications for management of couples with male infertility. Larger studies are needed to investigate whether weight loss is sufficient to improve pregnancy outcomes in couples affected by male infertility due to obesity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

https://doi.org/10.1210/jendso/bvac150.1446

PMON259 Weight Loss using a Formula Low Energy Diet Reduces Seminal Oxidative Stress in Men with Obesity and Oligospermia: a Randomised Controlled Study

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Microglia-derived TNFα induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma.

PMON259 Weight Loss using a Formula Low Energy Diet Reduces Seminal Oxidative Stress in Men with Obesity and Oligospermia: a Randomised Controlled Study