Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss.

Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via ß2-adrenergic receptor (ß2-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.

The relationship between HIV-1 neuroinflammation, neurocognitive impairment and encephalitis pathology: A systematic review of studies investigating post-mortem brain tissue.

The activities of HIV-1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV-associated neurocognitive disorders (HAND). The use of post-mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV-1-induced neuroinflammation in post-mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV-encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post-mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty-one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL-1ß and TNF-α were consistently associated with NCI/HIVE, whereas CCL2 and IL-6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba-1, IL-1ß and TNF-α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA-DR, IL-1 and IL-6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL-1ß and TNF-α were consistently associated with NCI/HIVE, while IL-6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV-1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.

Neurofilament Light Chain as a Biomarker of Neuronal Damage in Children With Malaria.

Malaria can cause brain injury. Neurofilament light chain (NfL) is a biomarker of neuronal damage. Here we examined longitudinal plasma NfL levels in children aged 1-12 years with uncomplicated and severe malaria from Mozambique. NfL levels were similar in all malaria cases at hospital admission. However, levels increased over time and the increment was significantly higher in severe malaria cases with neurological manifestations (ie, coma, impaired consciousness, or repeated seizures). NfL may be useful to identify and quantify brain injury in malaria.

Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS-CoV-2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell-derived CNS and PNS neurons with SARS-CoV-2. SARS-CoV-2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS-CoV-2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN-stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019 (COVID-19) related neuronal pathology and to test future preventive or therapeutic strategies.

METTL3-mediated ANXA2 inhibition confers neuroprotection in ischemic stroke: Evidence from in vivo and in vitro studies.

Given the important role of m6A, the most common and reversible mRNA modification, in the pathogenesis of ischemic stroke, this study investigates the mechanisms of m6A methyltransferase METTL3 in neuronal damage in ischemic stroke. In silico analysis was used to pinpoint the expression of ANXA2, which was verified in clinical peripheral blood samples. SD rats were used for middle cerebral artery occlusion (MCAO) establishment. The experimental data suggested that T lymphocytes were increased in peripheral blood samples of ischemic stroke patients and MCAO rats. The MCAO rats were treated with anti-ANXA2 alone or combined with RP101075 (T lymphocyte infiltration inhibitor), followed by brain injury assessment. Oxygen-glucose deprivation/reoxygenation (OGD/R) was induced in primary cortical neurons, where shRNAs targeting ANXA2 or METTL3, or overexpression plasmids of METTL3 were introduced to verify the regulatory function for METTL3. Inhibition of T lymphocyte migration to the ischemic brain reduced brain injury in MCAO rats and neuronal damage in OGD/R-exposed neurons. Ablation of ANXA2 in T lymphocytes inhibited the migration of T lymphocytes to the ischemic brain and reduced neuronal damage. Mechanistically, METTL3 reduced ANXA2 expression in T lymphocytes through m6A modification and inhibited p38MAPK/MMP-9 pathway activation, exerting protective effects against neuronal damage in ischemic stroke. Overall, this study reveals the neuroprotective effects of METTL3-mediated ANXA2/p38MAPK/MMP-9 inhibition against ischemic stroke.

The Role and Mechanism of Ambra1-Mediated Mitophagy in TDCPP-Exposed Mouse Hippocampal Neurons.

Tri(1,3-dichloro-2-propyl)phosphate (TDCPP) is one of the most widely used organophosphorus flame retardants in consumer products. TDCPP has been confirmed to be neurotoxic, but its mechanism has not been clarified and may be related to mitophagy. AMBRA1 can promote neurological autophagy, but whether AMBRA1 is involved in the mechanism of TDCPP-induced neurotoxicity has not been elucidated. In this study, the optimal neuronal damage model was established by exposing mice hippocampal neurons to TDCPP. Furthermore, on the basis of this model, siRNA was used to knock down AMBRA1. Combined with qRT-PCR and Western blot techniques, we identified AMBRA1-mediated mitophagy-induced neuronal damage in vitro mechanism. The experimental results indicated that TDCPP treatment for 24 h led to a decrease in the cell viability of mouse hippocampal neurons, causing neuronal damage. Meanwhile, TDCPP exposure increased autophagy marker proteins p62 and LC3B, and down-regulated mitochondrial DNA ND1 damage and TOMM20 protein, suggesting that TDCPP exposure promoted mitophagy. In addition, TDCPP exposure led to changes in the expression of AMBRA1 and the key factors of mitophagy, FUNDC1, PINK1, and PARKIN, whereas mitophagy was inhibited after knockdown of AMBRA1. The research results indicated that exposure to TDCPP induced neuronal damage and promoted mitophagy. The mechanism may be that AMBRA1 promoted mitophagy in neuronal cells through the PARKIN-dependent/non-dependent pathway. This study revealed the toxic effects of TDCPP on the nervous system and its potential molecular mechanisms, which provided important clues for further understanding the mechanism of action of AMBAR1-mediated mitophagy.

Hypothermia Attenuates Neurotoxic Microglial Activation via TRPV4.

Therapeutic hypothermia (TH) provides neuroprotection. However, the cellular mechanisms underlying the neuroprotective effects of TH are not fully elucidated. Regulation of microglial activation has the potential to treat a variety of nervous system diseases. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is activated by temperature stimulus at 27-35 °C. Although it is speculated that TRPV4 is associated with the neuroprotective mechanisms of TH, the role of TRPV4 in the neuroprotective effects of TH is not well understood. In the present study, we investigated whether hypothermia attenuates microglial activation via TRPV4 channels. Cultured microglia were incubated under normothermic (37 °C) or hypothermic (33.5 °C) conditions following lipopolysaccharide (LPS) stimulation. Hypothermic conditions suppressed the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and the number of phagocytic microglia. AMP-activated protein kinase (AMPK)-NF-κB signaling was inhibited under hypothermic conditions. Furthermore, hypothermia reduced neuronal damage induced by LPS-treated microglial cells. Treatment with TRPV4 antagonist in normothermic culture replicated the suppressive effects of hypothermia on microglial activation and microglia-induced neuronal damage. In contrast, treatment with a TRPV4 agonist in hypothermic culture reversed the suppressive effect of hypothermia. These findings suggest that TH suppresses microglial activation and microglia-induced neuronal damage via the TRPV4-AMPK-NF-κB pathway. Although more validation is needed to consider differences according to age, sex, and specific central nervous system regions, our findings may offer a novel therapeutic approach to complement TH.

Photoaged Nanopolystyrene Affects Neurotransmission to Induce Transgenerational Neurotoxicity in Caenorhabditis elegans.

Nanopolystyrene (NPS), a frequently employed nanoplastic, is an emerging environmental contaminant known to cause neurotoxicity in various organisms. However, the potential for transgenerational neurotoxic effects, especially from photoaged NPS (P-NPS), remains underexplored. This study investigated the aging of virgin NPS (V-NPS) under a xenon lamp to simulate natural sunlight exposure, which altered the physicochemical characteristics of the NPS. The parental generation (P0) of Caenorhabditis elegans was exposed to environmental concentrations (0.1-100 µg/L) of V-NPS and P-NPS, with subsequent offspring (F1-F4 generations) cultured under NPS-free conditions. Exposure to 100 µg/L P-NPS resulted in more pronounced deterioration in locomotion behavior in the P0 generation compared to V-NPS; this deterioration persisted into the F1-F2 generations but returned to normal in the F3-F4 generations. Additionally, maternal exposure to P-NPS damaged dopaminergic, glutamatergic, and serotonergic neurons in subsequent generations. Correspondingly, there was a significant decrease in the levels of dopamine, glutamate, and serotonin, associated with reduced expression of neurotransmission-related genes dat-1, eat-4, and tph-1 in the P0 and F1-F2 generations. Further analysis showed that the effects of P-NPS on locomotion behavior were absent in subsequent generations of eat-4(ad572), tph-1(mg280), and dat-1(ok157) mutants, highlighting the pivotal roles of these genes in mediating P-NPS-induced transgenerational neurotoxicity. These findings emphasize the crucial role of neurotransmission in the transgenerational effects of P-NPS on locomotion behavior, providing new insights into the environmental risks associated with exposure to photoaged nanoplastics.

Natural compounds for oxidative stress and neuroprotection in schizophrenia: composition, mechanisms, and therapeutic potential.

OBJECTIVE: An imbalance between the generation of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms is believed to be a critical factor in the development of schizophrenia (SCZ) like neurological illnesses. Understanding the roles of ROS in the development of SCZ and the potential activity of natural antioxidants against SCZ could lead to more effective therapeutic options for the prevention and treatment of the illness. METHODS: SCZ is a mental disorder characterised by progressive impairments in working memory, attention, and executive functioning. In present investigation, we summarized the experimental findings for understanding the role of oxidative stress (OS) in the development of SCZ and the potential neuroprotective effects of natural antioxidants in the treatment of SCZ. RESULTS: Current study supports the use of the mentioned antioxidant natural compounds as a potential therapeutic candidates for the treatment of OS mediated neurodegeneration in SCZ. DISCUSSION: Elevated levels of harmful ROS and reduced antioxidant defense mechanisms are indicative of increased oxidative stress (OS), which is associated with SCZ. Previous research has shown that individuals with SCZ, including non-medicated, medicated, first-episode, and chronic patients, exhibit decreased levels of total antioxidants and GSH. Additionally, they have reduced antioxidant enzyme levels such as catalase (CAT), glutathione (GPx), and, superoxide dismutase (SOD) and lower serum levels of brain-derived neurotrophic factor (BDNF) in their brain tissue. The mentioned natural antioxidants may assist in reducing oxidative damage in individuals with SCZ and increasing BDNF expression in the brain, potentially improving cognitive function and learning ability.

SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

Microcurrent Therapy Mitigates Neuronal Damage and Cognitive Decline in an Alzheimer's Disease Mouse Model: Insights into Mechanisms and Therapeutic Potential.

Alzheimer's disease (AD) presents a significant challenge due to its multifaceted nature, characterized by cognitive decline, memory loss, and neuroinflammation. Though AD is an extensively researched topic, effective pharmacological interventions remain elusive, prompting explorations into non-pharmacological approaches. Microcurrent (MC) therapy, which utilizes imperceptible currents, has emerged as a potent clinical protocol. While previous studies have focused on its therapeutic effects, this study investigates the impact of MC on neuronal damage and neuroinflammation in an AD mouse model, specifically addressing potential side effects. Utilizing 5xFAD transgenic mice, we examined the effects of MC therapy on neuronal integrity and inflammation. Our findings suggest that MC therapy attenuates memory impairment and reduces neurodegeneration, as evidenced by improved performance in memory tests and the preservation of the neuronal structure. Additionally, MC therapy significantly decreases amyloid-beta (Aß) plaque deposition and inhibits apoptosis, indicating its potential to mitigate AD pathology. This study determined that glial activation is effectively reduced by using MC therapy to suppress the TLR4-MyD88-NFκB pathway, which consequently causes the levels of inflammatory factors TNF-α, IL-1ß, and IL-6 to decrease, thus implicating TLR4 in neurodegenerative disease-related neuroinflammation. Furthermore, while our study did not observe significant adverse effects, a further clinical trial into potential side effects and neuroinflammatory responses associated with MC therapy is warranted.

Regulatory mechanism of miR-20a-5p in neuronal damage and inflammation in lipopolysaccharide-induced BV2 cells and MPTP-HCl-induced Parkinson's disease mice.

BACKGROUND: Parkinson's disease (PD) is a prevailing neurodegenerative disorder increasingly affecting the elderly population. The involvement of microRNAs (miRNAs) in PD has been confirmed. We sought to explore the molecular mechanism of miR-20a-5p in PD. METHODS: Lipopolysaccharide (LPS)-induced BV2 cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP-HCl)-induced PD mouse model were established. miR-20a-5p, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and IL-10 expression in BV2 cells was examined by reverse transcription - quantitative polymerase chain reaction. Cell viability was assessed by MTT assay. The apoptotic rate and levels of Bcl-2, Bax, cleaved caspase-3, and signal transducer and activator of transmission (STAT)3 were examined by flow cytometry and Western blot. Bioinformatics software predicted the potential binding sites of miR-20a-5p and STAT3. Dual-luciferase experiment verified the binding relationship. Iba1-positive and tyrosine hydroxylase (TH)-positive cell numbers in substantia nigra pars compacta were detected by immunohistochemistry. The effect of miR-20a-5p on motor function in MPTP-induced PD mice was detected by Rota-rod test, Pole test, Traction test and Beam-crossing task. RESULTS: miR-20a-5p was under-expressed in LPS-induced BV2 cells. Overexpression of miR-20a-5p increased the viability of LPS-induced BV2 cells and reduced apoptosis rates. Moreover, overexpression of miR-20a-5p reduced cleaved caspase-3, Bax, iNOS, IL-6, and TNF-α and increased Bcl-2 and TGF-ß1, and IL-10. miR-20a-5p targeted STAT3. STAT3 overexpression partially reversed miR-20a-5p overexpression-mediated effects on LPS-induced BV2 cell viability, apoptosis, and inflammatory responses. miR-20a-5p overexpression inhibited MPTP-induced STAT3 and α-synuclein levels, microglia activation, and inflammatory response, and reduced the loss of TH-positive cells in mice. miR-20a-5p overexpression ameliorated MPTP-induced dyskinesia in PD model mice. CONCLUSION: miR-20a-5p alleviates neuronal damage and suppresses inflammation by targeting STAT3 in PD.

Effects of HMGB1/RAGE/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic-ischemic brain damage.

Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic-ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high-mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen-glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20 mg/kg) reduced the expression of microglial pyroptosis-related proteins, including caspase-1, the N-terminus fragment of gasdermin D (N-GSDMD), and pyroptosis-related inflammatory factors, such as interleukin (IL) -1ß and IL-18. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72 h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD-induced pyroptosis is mediated by HMGB1/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS-ZM1, 1 mg/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074-Me (5 mg/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1/RAGE/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1/RAGE/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.

Neurological symptoms and neuronal damage markers in acute COVID-19: Is there a correlation? A pilot study.

A wide spectrum of neurological symptoms (NS) has been described in patients with COVID-19. We examined the plasma levels of neuron-specific enolase (NSE) and neurofilament light chain (NFL) together, as neuronal damage markers, and their relationships with clinical severity in patients with NS at acute COVID-19. A total of 20 healthy controls and 59 patients with confirmed COVID-19 were enrolled in this pilot prospective study. Serum NSE and NFL levels were measured by using the enzyme-linked immunoassay method from serum samples. Serum NSE levels were found to be significantly higher in the severe group than in the nonsevere group (p = 0.034). However, serum NFL levels were similar between the control and disease groups (p > 0.05). For the mild group, serum NFL levels were significantly higher in patients with the sampling time ≥5 days than in those with the sampling time <5 days (p = 0.019). However, no significant results for NSE and NFL were obtained in patients with either single or multiple NS across the groups (p > 0.05). Increased serum NSE levels were associated with disease severity regardless of accompanied NS in patients with acute COVID-19 infection. However, serum NFL levels may have a role at the subacute phase of COVID-19.

The Impact of Cerebral Ischemia on Antioxidant Enzymes Activity and Neuronal Damage in the Hippocampus.

Cerebral ischemia and subsequent reperfusion, leading to reduced blood supply to specific brain areas, remain significant contributors to neurological damage, disability, and mortality. Among the vulnerable regions, the subcortical areas, including the hippocampus, are particularly susceptible to ischemia-induced injuries, with the extent of damage influenced by the different stages of ischemia. Neural tissue undergoes various changes and damage due to intricate biochemical reactions involving free radicals, oxidative stress, inflammatory responses, and glutamate toxicity. The consequences of these processes can result in irreversible harm. Notably, free radicals play a pivotal role in the neuropathological mechanisms following ischemia, contributing to oxidative stress. Therefore, the function of antioxidant enzymes after ischemia becomes crucial in preventing hippocampal damage caused by oxidative stress. This study explores hippocampal neuronal damage and enzymatic antioxidant activity during ischemia and reperfusion's early and late stages.

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway.

Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H2S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H2S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H2S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H2S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H2S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H2S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H2S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H2S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.

Silencing of miR-132-3p protects against neuronal injury following status epilepticus by inhibiting IL-1ß-induced reactive astrocyte (A1) polarization.

Mesial temporal lobe epilepsy (MTLE) is one of the most common refractory epilepsies and is usually accompanied by a range of brain pathological changes, such as neuronal injury and astrocytosis. Naïve astrocytes are readily converted to cytotoxic reactive astrocytes (A1) in response to inflammatory stimulation, suppressing the polarization of A1 protects against neuronal death in early central nervous system injury. Our previous study found that pro-inflammatory cytokines and miR-132-3p (hereinafter referred to as "miR-132") expression were upregulated, but how miR-132 affected reactive astrocyte polarization and neuronal damage during epilepsy is not fully understood. Here, we aimed to explore the effect and mechanism of miR-132 on A1 polarization. Our results confirmed that A1 markers were significantly elevated in the hippocampus of MTLE rats and IL-1ß-treated primary astrocytes. In vivo, knockdown of miR-132 by lateral ventricular injection reduced A1 astrocytes, neuronal loss, mossy fiber sprouting, and remitted the severity of status epilepticus and the recurrence of spontaneous recurrent seizures. In vitro, the neuronal cell viability and axon length were reduced by additional treatment with A1 astrocyte conditioned media (ACM), and downregulation of astrocyte miR-132 rescued the inhibition of cell activity by A1 ACM, while the length of axons was further inhibited. The regulation of miR-132 on A1 astrocytes may be related to its target gene expression. Our results show that interfering with astrocyte polarization may be a breakthrough in the treatment of refractory epilepsy, which may extend to the research of other astrocyte polarization-mediated brain injuries.

Apelin-13 Improves Cognitive Impairment and Repairs Hippocampal Neuronal Damage by Activating PGC-1α/PPARγ Signaling.

Alzheimer's disease (AD) is a complex neurodegenerative disease that is prevalent around the world. Both Apelin-13 and proliferator-activated receptor-γ (PPARγ)/PPARγ co-activator 1α (PGC-1α) are regarded as candidate targets for treating AD. The investigation examined whether Apelin-13 exerts neuroprotective effects via PGC-1α/PPARγ signaling. In this study, Apelin-13 improved cognitive deficits in AD mice, while SR-18,292 (a PGC-1α inhibitor) interfered with the therapeutic effects of Apelin-13. Mechanistically, Apelin-13, PGC-1α and PPARγ were decreased in AD mice and oxygen-glucose deprivation (OGD)-induced neuronal cells. Apelin-13 bound to PGC-1α and negatively regulated the expression of PGC-1α and PPARγ. In turn, PGC-1α accelerated the accumulation of Apelin-13 and PPARγ. Additionally, neuronal apoptosis was inhibited, and the abundance of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase 3) was induced. The content of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) fluctuated. The level of inflammatory factors (interleukin-6, IL-6, IL-10, tumor necrosis factor-α, TNF-α) was regulated. In short, Apelin-13 exerted anti-apoptosis, anti-oxidant stress and anti-inflammatory effects. Interestingly, PGC-1α silencing promoted neuronal apoptosis, oxidant stress and inflammation, and overexpression of PGC-1α exhibited the opposite. More importantly, inhibition of PGC-1α attenuated Apelin-13-enhanced cognitive impairment and neuronal damage. Therefore, our findings suggested that Apelin-13 exerted neuroprotective effects in part via the PGC-1α/PPARγ pathway.

Anticonvulsant Effects of Royal Jelly in Kainic Acid-Induced Animal Model of Temporal Lobe Epilepsy Through Antioxidant Activity.

Temporal lobe epilepsy (TLE) is the most common form of partial and drug-resistant epilepsy, characterized by recurrent seizures originating from temporal lobe structures like the hippocampus. Hippocampal sclerosis and oxidative stress are two important factors in the pathogenesis of TLE that exacerbate epileptic seizures in this form of epilepsy. Recently, royal jelly (RJ) shown to have neuroprotective and antioxidant activities in several neurodegenerative models. Therefore, the aim of the present study was to investigate the pretreatment effect of RJ on epileptic seizures, hippocampal neuronal loss, and oxidative stress in the rat model of kainic acid (KA)-induced TLE. To this aim, 40 male Wistar rats weighing 200-250 g were divided into 4 groups, including control, vehicle, KA, and RJ + KA. Rats received RJ (150 mg/kg/day) for 14 days before induction of TLE with KA. Epileptic behaviors were evaluated according to Racine's scale. Oxidative stress markers including, malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant capacity (TAC) as well as neuronal loss in the CA1 region of the hippocampus (using Nissl staining) were evaluated in all groups. Our findings showed that RJ pretreatment significantly reduced the seizure score and increased the latency to the first seizure. RJ also reduced MDA and TOS while increasing TAC. In addition, RJ reversed neuronal damage in the hippocampal CA1 and CA3 areas. In conclusion, our results suggest that RJ has anticonvulsant and neuroprotective effects in KA induced TLE via its antioxidative properties.

MDMA targets miR-124/MEKK3 via MALAT1 to promote Parkinson's disease progression.

BACKGROUND: Parkinson's disease (PD) is a well-known neurodegenerative disease that is usually caused by the progressive loss of dopamine neurons and the formation of Lewy vesicles. 3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause damage to human substantia nigra neurons and an increased risk of PD, but the exact molecular mechanisms need further investigation. METHODS: MPTP- and MPP+-induced PD cells and animal models were treated with Nissl staining to assess neuronal damage in the substantia nigra (SN) area; immunohistochemistry to detect TH expression in the SN; TUNEL staining to detect apoptosis in the SN area; Western blotting to detect the inflammatory factors NF-κB, TNF-α, IL-6 and mitogen-activated protein kinase kinase kinase 3 (MEKK3); Griess assay for NO; RT‒qPCR for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-124 expression; Cell proliferation was assessed by CCK-8. Dual luciferase reporter genes were used to verify targeting relationships. RESULTS: MDMA promoted MALAT1 expression, and knockdown of MALAT1 alleviated the MDMA-induced inhibition of SH-SY5Y cell proliferation, inflammation, NO release, SN neuronal injury, and TH expression inhibition. Both inhibition of miR-124 and overexpression of MEKK3 reversed the neuroprotective effects exhibited by knockdown of MALAT1. CONCLUSION: MDMA promotes MALAT1 expression and inhibits the targeted downregulation of MEKK3 by miR-124, resulting in upregulation of the expression of MEKK3 and finally jointly promoting PD progression.