The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

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Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease.

Every year stroke claims more than 6 million lives worldwide. The majority of them are ischemic stroke. Small molecule-based therapeutics for ischemic stroke has attracted a lot of attention, but none has been shown to be clinically useful so far. Hypoxia-inducible factor-1 (HIF-1) plays a crucial role in the transcriptional adaptation of cells to hypoxia. Small molecule-based hypoxia-mimetic agents either stabilize HIF-1α via HIF-prolyl hydroxylases (PHDs) inhibition or through other mechanisms. In both the cases, these agents have been shown to confer ischemic neuroprotection in vitro and in vivo. The agents which act via PHD inhibition are mainly classified into iron chelators, iron competitors, and 2 oxoglutarate (2OG) analogs. This review discusses HIF structure and key players in the HIF-1 degradation pathway as well as the genes, proteins and chemical molecules that are connected to HIF-1 and how they affect cell survival following ischemic injury. Furthermore, this review gives a summary of studies that used PHD inhibitors and other HIF-1α stabilizers as hypoxia-mimetic agents for the treatment of ischemic injury.

/pdf/hypoxia-mimetic-agents-for-ischemic-stroke-1f1j2nw4x8.pdf

Hypoxia Mimetic Agents for Ischemic Stroke

Ischemic stroke (IS) is one of the major types of cerebrovascular diseases causing neurological morbidity and mortality worldwide. In the pathophysiological process of IS, microglia play a beneficial role in tissue repair. However, it could also cause cellular damage, consequently leading to cell death. Inflammation is characterized by the activation of microglia, and increasing evidence showed that autophagy interacts with inflammation through regulating correlative mediators and signaling pathways. In this paper, we summarized the beneficial and harmful effects of microglia in IS. In addition, we discussed the interplay between microglia autophagy and ischemic inflammation, as along with its application in the treatment of IS. We believe this could help to provide the theoretical references for further study into IS and treatments in the future.

/pdf/microglia-autophagy-in-ischemic-stroke-a-double-edged-sword-gjuysixa.pdf

Microglia autophagy in ischemic stroke: A double-edged sword

Currently, there is no efficient therapy for spinal cord injury (SCI). Anoxemia after SCI is a key problem, which leads to tissue destruction, while hypoxia after SCI induces cell injury along with inflammation. Mixed-lineage kinase domain-like protein (MLKL) is a critical signal molecule of necroptosis, and mitochondrial dysfunction is regarded as one of the most pivotal events after SCI. Based on the important role of MLKL in cell damage and potential role of mitochondrial dysfunction, our study focuses on the regulation of MLKL by Necrosulfonamide (NSA) in mitochondrial dysfunction of oxygen-glucose deprivation (OGD)-induced cell damage and SCI-mice, which specifically blocks the MLKL. Our results showed that NSA protected against a decrease in the mitochondrial membrane potential, adenosine triphosphate, glutathione, and superoxide dismutase levels and an increase in reactive oxygen species and malonyldialdehyde levels. NSA also improved the locomotor function in SCI-mice and OGD-induced spinal neuron injury through inhibition of MLKL activation independently of receptor-interacting protein kinase 3 (RIP3) phosphorylation. Besides the protective effects, NSA exhibited a therapeutic window. The optimal treatment time was within 12 h after the injury in the SCI-mice model. In conclusion, our data suggest a close association between the NSA level inhibiting p-MLKL independently of RIP3 phosphorylation and induction of neurological impairment by improving antioxidative capacity after SCI. NSA ameliorates neurological impairment in SCI through inhibiting MLKL-dependent necroptosis. It also provides a theoretical basis for further research and application of NSA in the treatment of SCI.

/pdf/necrosulfonamide-ameliorates-neurological-impairment-in-2rdxafvfi9.pdf

Necrosulfonamide Ameliorates Neurological Impairment in Spinal Cord Injury by Improving Antioxidative Capacity.

Purpose Reoxygenation after hypoxia can increase reactive oxygen species and upregulate autophagy. We determined, for the first time, the impact of elevated IOP on hypoxia induction, superoxide accumulation, and autophagy in a bead model of glaucoma. Method Ocular hypertension was achieved with magnetic bead injection into the anterior chamber. Before mice were killed, they were injected with pimonidazole for hypoxia detection and dihydroethidium (DHE) for superoxide detection. Total retinal ganglion cells (RGCs) and optic nerve (ON) axons were quantified, total glutathione (GSH) was measured, and retinal and ON protein and mRNA were analyzed for hypoxia (Hif-1α and Hif-2α), autophagy (LC3 and p62), and SOD2. Results With IOP elevation (P < 0.0001), the retina showed significantly (P < 0.001) decreased GSH compared with control, and a significant decrease (P < 0.01) in RGC density compared with control. Pimonidazole-positive Muller glia, microglia, astrocytes, and RGCs were present in the retinas after 4 weeks of ocular hypertension but absent in both the control and after only 2 weeks of ocular hypertension. The ON showed significant axon degeneration (P < 0.0001). The mean intensity of DHE in the ganglion cell layer and ON significantly increased (P < 0.0001). The ratio of LC3-II to LC3-I revealed a significant increase (P < 0.05) in autophagic activity in hypertensive retinas compared with control. Conclusions We report a novel observation of hypoxia and a significant decrease in GSH, likely contributing to superoxide accumulation, in the retinas of ocular hypertensive mice. The significant increase in the ratio of LC3-II to LC3-I suggests autophagy induction.

Evidence of Hypoxic Glial Cells in a Model of Ocular Hypertension.

Effects of molecular hydrogen intervention on the gut microbiome in methamphetamine abusers with mental disorder

Microglial cells are phagocytic cells of the central nervous system (CNS) and have been proposed to be a primary component of the innate immune response and maintain efficient CNS homeostasis. Microglial cells are activated during various phases of tissue repair and participate in various pathological conditions in the CNS. Following spinal cord injury (SCI), anoxemia is a key problem that results in tissue destruction. Hypoxia‑inducible factor 1‑α (HIF‑1α) may protect hypoxic cells from apoptosis or necrosis under ischemic and anoxic conditions. However, numerous studies have revealed that hypoxia upregulates HIF‑1α expression leading to the death of microglial cells. The present study investigated the alterations in HIF‑1α expression levels and the mechanism of autophagic cell death mediated by HIF‑1α in microglial cells induced by hypoxia. Hypoxia was demonstrated to induce HIF‑1α expression and autophagic cell death in microglial cells. Enhanced autophagy reduced cell death during the initial stages by restraining the functions of autophagy‑associated genes (microtubule‑associated protein 1A/1B‑light chain 3 phosphatidylethanolamine conjugate and Beclin‑1) and modulating the expression of inflammatory cytokines (tumor necrosis factor‑α and interleukin‑1β). Target value was determined by Cell Counting Kit 8 and cell death by flow cytometry. Transmission electron microscopy, immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction, western blotting, and ELISA were used for further analysis. However, increased expression of HIF‑1α induced cell death and autophagic cell death in microglial cells. Furthermore, the effects of the HIF‑1α inhibitor 2‑methoxyestradiol and HIF‑1α small interfering RNA on the death and autophagy of microglial cells in vitro were investigated. These investigations revealed the suppression of autophagy, the decrease of cell viability and the increase of inflammatory cytokines results from HIF‑1α inhibition or HIF‑1α silencing. In conclusion, the results indicated that appropriate expression of HIF‑1α can ameliorate autophagic cell death of microglial cells associated with hypoxia, and may provide a novel therapeutic approach for SCI associated with microglial cell activation.

/pdf/role-of-hypoxia-inducible-factor-1a-in-autophagic-cell-death-dgaql1wx04.pdf

Role of hypoxia‑inducible factor‑1α in autophagic cell death in microglial cells induced by hypoxia.

Methamphetamine (METH) abuse causes irreversible damage to the central nervous system and leads to psychiatric symptoms including depression. Notably, METH-induced hyperthermia is a crucial factor in the development of these symptoms, as it aggravates METH-induced neurotoxicity. However, the role of hyperthermia in METH-induced depression-like behaviors needs to be clarified. In the present study, we treated mice with different doses of METH under normal (NAT) or high ambient temperatures (HAT). We found that HAT promoted hyperthermia after METH treatment and played a key role in METH-induced depression-like behaviors in mice. Intriguingly, chronic METH exposure (10 mg/kg, 7 or 14 days) or administration of an escalating-dose (2 ∼ 15 mg/kg, 3 days) of METH under NAT failed to induce depression-like behaviors. However, HAT aggravated METH-induced damage of hippocampal synaptic plasticity, reaction to oxidative stress, and neuroinflammation. Molecular hydrogen acts as an antioxidant and anti-inflammatory agent and has been shown to have preventive and therapeutic applicability in a wide range of diseases. Coral calcium hydride (CCH) is a newly identified hydrogen-rich powder which produces hydrogen gas gradually when exposed to water. Herein, we found that CCH pretreatment significantly attenuated METH-induced hyperthermia, and administration of CCH after METH exposure also inhibited METH-induced depression-like behaviors and reduced the hippocampal synaptic plasticity damage. Moreover, CCH effectively reduced the activity of lactate dehydrogenase and decreased malondialdehyde, TNF-α and IL-6 generation in hippocampus. These results suggest that CCH is an efficient hydrogen-rich agent, which has a potential therapeutic applicability in the treatment of METH abusers.

The Role of Hyperthermia in Methamphetamine-Induced Depression-Like Behaviors: Protective Effects of Coral Calcium Hydride

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Effects of molecular hydrogen intervention on the gut microbiome in methamphetamine abusers with mental disorder

Role of hypoxia‑inducible factor‑1α in autophagic cell death in microglial cells induced by hypoxia.

The Role of Hyperthermia in Methamphetamine-Induced Depression-Like Behaviors: Protective Effects of Coral Calcium Hydride