Dexmedetomidine Inhibits Hippocampal Neuronal Damage Caused by Persistent Isoflurane-Induced Hypotension in Rat Model of Chronic Cerebral Hypoperfusion.

Purpose The purpose of this study was to investigate the effect of dexmedetomidine (DEX) on hypotension-induced neuronal damage in a chronic cerebral hypoperfusion (CCH) model of rats, an established model of cerebral white matter lesions (WML) in humans, which is prevalent in the elderly and closely related to cognitive decline. Methods The CCH model rats were randomly assigned to one of four groups: normotension + no DEX (NN) group (n = 6), normotension + DEX (ND) group (n = 6), hypotension + no DEX (HN) group (n = 6), or hypotension + DEX (HD) group (n = 6). Under isoflurane anesthesia, mean arterial blood pressure was maintained at or above 80 mmHg (normotension) or below 60 mmHg (hypotension) for a duration of two hours. The DEX groups received 50 µg of DEX intraperitoneally. Two weeks later, the Y-maze test and, after preparing brain slices, immunohistochemical staining were performed using antibodies against neuronal nuclei (NeuN), microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP), and Ionized calcium-binding adapter molecule 1 (Iba1). Results Behavioral observations showed no significant differences among the groups. Significant reductions of both NeuN-positive cells and the MAP2-positive area were found in the hippocampal CA1 in the HN group compared with NN and ND groups, but not in the HD group. GFAP and Iba-1-positive areas were significantly increased in the HN group, but not in the HD group. Conclusion DEX significantly ameliorated hypotension-induced neuronal damage and both astroglial and microglial activation in the CA1 region of CCH rats.

LanCL1 protects developing neurons from long-term isoflurane anesthesia-induced neurotoxicity.

Research has revealed that prolonged or repeated exposure to isoflurane, a common general anesthetic, can lead to cognitive and behavioral deficiencies, particularly in early life. The brain contains a wealth of LanCL1, an antioxidant enzyme that is thought to mitigate oxidative stress. Nevertheless, its precise function in mammals remains uncertain. This study uncovered a decrease in the expression of LanCL1 due to prolonged isoflurane anesthesia, accompanied by anesthesia-induced neurotoxicity in vivo and in vitro. To better understand LanCL1's essential function, LanCL1 overexpressing adenoviruses were employed to increase LanCL1 levels. The outcomes were analyzed using western blot and immunofluorescence methods. According to the findings, extended exposure to isoflurane anesthesia may lead to developmental neurotoxicity in vivo and in vitro. The anesthesia-induced neurotoxicity was concomitant with a reduction in LanCL1 expression. Moreover, the study revealed that overexpression of LanCL1 can mitigate the neurotoxic effects of isoflurane anesthesia, resulting in improved synaptic growth, less reactive oxygen species enhanced cell viability and rescued memory deficits in the developing brain. In conclusion, prolonged anesthesia-induced LanCL1 deficiency could be responsible for neurotoxicity and subsequent cognitive impairments in the developing brain. Additional LanCL1 counteracts this neurotoxic effect and protects neurons from long-term isoflurane anesthesia.

Neurotoxicity of tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) through the GABAergic and serotonergic neurotransmission in Caenorhabditis elegans.

Tetrabromobisphenol-A-bis(2,3-dibromopropyl ether) (TBBPA-BDBPE), a novel additive brominated flame retardant, is being developed for use in polyolefin and copolymers. Despite its emerging application, the neurotoxicity and mechanisms of action of TBBPA-BDBPE remain unexplored. Caenorhabditis elegans was utilized as the model organism to study the neurotoxic effects of TBBPA-BDBPE across environmental concentrations ranging from 0 to 100 µg/L. This investigation focused on various toxicological endpoints such as locomotive behavior, neuronal injury, neurotransmitter transmission, and the regulation of nervous system-related gene expression. Acute exposure to TBBPA-BDBPE at concentrations of 10-100 µg/L significantly impaired nematode movement, indicating potential neurotoxicity. In transgenic nematodes, this exposure also caused damage to γ-aminobutyric acid (GABAergic) and serotonergic neurons, along with notable changes in the levels of GABAergic and serotonergic neurotransmitters. Further molecular studies indicated alterations in neurotransmission-related genes (cat-4, mod-1, unc-25, and unc-47). Molecular docking analysis confirmed the binding affinity of TBBPA-BDBPE to key neurotransmission proteins-CAT-4, MOD-1, UNC-25, and UNC-47. These findings demonstrate that TBBPA-BDBPE exerts neurotoxic effects by impacting GABAergic and serotonergic neurotransmission in nematodes. This study provides new insights into the potential environmental risks of TBBPA-BDBPE.

Astragaloside IV mediates radiation-induced neuronal damage through activation of BDNF-TrkB signaling.

BACKGROUND: Electromagnetic radiation is relevant to human life, and radiation can trigger neurodegenerative diseases by altering the function of the central nervous system through oxidative stress, mitochondrial dysfunction, and protein degradation. Astragaloside IV (AS-IV) is anti-oxidative, anti-apoptotic, activates the BDNF-TrkB pathway and enhances synaptic plasticity in radiated mice, which can exert its neuroprotection. However, the exact molecular mechanisms are still unclear. PURPOSE: This study investigated whether AS-IV could play a neuroprotective role by regulating BDNF-TrkB pathway in radiation damage and its underlying molecular mechanisms. METHODS: Transgenic mice (Thy1-YFP line H) were injected with AS-IV (40 mg/kg/day body weight) by intraperitoneal injection daily for 4 weeks, followed by X-rays. PC12 cells and primary cortical neurons were also exposed to UVA after 24 h of AS-IV treatment (25 µg/ml and 50 µg/ml) in vitro. The impact of radiation on learning and cognitive functions was visualized in the Morris water maze assay. Subsequently, Immunofluorescence and Golgi-Cox staining analyses were utilized to investigate the structural damage of neuronal dendrites and the density of dendritic spines. Transmission electron microscopy was performed to examine how the radiation affected the ultrastructure of neurons. Finally, western blotting analysis and Quantitative RT-PCR were used to evaluate the expression levels and locations of proteins in vitro and in vivo. RESULTS: Radiation induced BDNF-TrkB signaling dysregulation and decreased the levels of neuron-related functional genes (Ngf, Bdnf, Gap-43, Ras, Psd-95, Arc, Creb, c-Fos), PSD-95 and F-actin, which subsequently led to damage of neuronal ultrastructure and dendrites, loss of dendritic spines, and decreased dendritic complexity index, contributing to spatial learning and memory deficits. These abnormalities were prevented by AS-IV treatment. In addition, TrkB receptor antagonists antagonized these neuroprotective actions of AS-IV. 7,8-dihydroxyflavone and AS-IV had neuroprotective effects after radiation. CONCLUSION: AS-IV inhibits morphological damage of neurons and cognitive dysfunction in mice after radiation exposure, resulting in a neuroprotective effect, which were mediated by activating the BDNF-TrkB pathway.

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.

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.

Ginsenoside Rg3 attenuates neuroinflammation and hippocampal neuronal damage after traumatic brain injury in mice by inactivating the NF-kB pathway via SIRT1 activation.

This investigation examined the potential of ginsenoside Rg3 in addressing traumatic brain injury (TBI). A TBI mouse model underwent treatment with ginsenoside Rg3 and nicotinamide (NAM). Neurological and motor functions were assessed using modified neurological severity score and rotarod tests. Brain water content in mice was detected. Primary mouse microglia were exposed to lipopolysaccharide (LPS), ginsenoside Rg3, and NAM. Nissl and immunofluorescence staining were utilized to investigate hippocampal damage, and localization of P65, Iba1 and INOS in microglia. Hippocampal neurons were grown in a culture medium derived from microglia. CCK-8 and TUNEL assays were employed to evaluate the viability and apoptosis of hippocampal neurons. Proinflammatory factors and proteins were tested using ELISA, western blot and immunofluorescence staining. As a result, ginsenoside Rg3 enhanced neurological and motor functions in mice post-TBI, reduced brain water content, alleviated hippocampal neuronal neuroinflammation and damage, activated SIRT1, and deactivated the NF-kB pathway. In LPS-stimulated microglia, ginsenoside Rg3 diminished inflammation, activated SIRT1, deactivated the NF-kB pathway, and facilitated nuclear localization of P65 and co-localization of Iba1 and INOS. The effects of ginsenoside Rg3 were countered by NAM in both TBI mice and LPS-stimulated microglia. Hippocampal neurons cultured in a medium containing LPS, ginsenoside Rg3, and NAM-treated microglia showed improved viability and reduced apoptosis compared to those cultured in a medium with LPS and ginsenoside Rg3-treated microglia alone. Ginsenoside Rg3 was effective in reducing neuroinflammation and damage in hippocampal neurons following TBI by modulating the SIRT1/NF-kB pathway, suggesting its potential as a therapeutic agent for TBI.

Pathological mechanisms and future therapeutic directions of thrombin in intracerebral hemorrhage: a systematic review.

Intracerebral hemorrhage (ICH), a common subtype of hemorrhagic stroke, often causes severe disability or death. ICH induces adverse events that might lead to secondary brain injury (SBI), and there is currently a lack of specific effective treatment strategies. To provide a new direction for SBI treatment post-ICH, the systematic review discussed how thrombin impacts secondary injury after ICH through several potentially deleterious or protective mechanisms. We included 39 studies and evaluated them using SYRCLE's ROB tool. Subsequently, we explored the potential molecular mechanisms of thrombin-mediated effects on SBI post-ICH in terms of inflammation, iron deposition, autophagy, and angiogenesis. Furthermore, we described the effects of thrombin in endothelial cells, astrocytes, pericytes, microglia, and neurons, as well as the harmful and beneficial effects of high and low thrombin concentrations on ICH. Finally, we concluded the current research status of thrombin therapy for ICH, which will provide a basis for the future clinical application of thrombin in the treatment of ICH.

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.

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.

Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Assessing Stress Induced by Fluid Shifts and Reduced Cerebral Clearance during Robotic-Assisted Laparoscopic Radical Prostatectomy under Trendelenburg Positioning (UroTreND Study).

In addition to general anesthesia and mechanical ventilation, robotic-assisted laparoscopic radical prostatectomy (RALP) necessitates maintaining a capnoperitoneum and placing the patient in a pronounced downward tilt (Trendelenburg position). While the effects of the resulting fluid shift on the cardiovascular system seem to be modest and well tolerated, the effects on the brain and the blood-brain barrier have not been thoroughly investigated. Previous studies indicated that select patients showed an increase in the optic nerve sheath diameter (ONSD), detected by ultrasound during RALP, which suggests an elevation in intracranial pressure. We hypothesize that the intraoperative fluid shift results in endothelial dysfunction and reduced cerebral clearance, potentially leading to transient neuronal damage. This prospective, monocentric, non-randomized, controlled clinical trial will compare RALP to conventional open radical prostatectomy (control group) in a total of 50 subjects. The primary endpoint will be the perioperative concentration of neurofilament light chain (NfL) in blood using single-molecule array (SiMoA) as a measure for neuronal damage. As secondary endpoints, various other markers for endothelial function, inflammation, and neuronal damage as well as the ONSD will be assessed. Perioperative stress will be evaluated by questionnaires and stress hormone levels in saliva samples. Furthermore, the subjects will participate in functional tests to evaluate neurocognitive function. Each subject will be followed up until discharge. Conclusion: This trial aims to expand current knowledge as well as to develop strategies for improved monitoring and higher safety of patients undergoing RALP. The trial was registered with the German Clinical Trials Register DRKS00031041 on 11 January 2023.

Olfactory three needle regulates the proliferation of olfactory bulb neural stem cells and ameliorates brain injury after subarachnoid hemorrhage by regulating Wnt/ß-catenin signaling.

Background: Subarachnoid hemorrhage (SAH) is a serious cerebrovascular emergency. The incidence of SAH and hazard ratio of death increase with age. Objective: In this study, we aimed to observe the effects and potential mechanisms of olfactory three needle (OTN) on cognitive impairment, neuronal activity, and neural stem cell differentiation in SAH rats. Methods: Sprague-Dawley (SD) rats were randomly divided into five groups: Sham, SAH group, SAH + Nimodipine (NMP) group, and SAH + OTN group. The rats in the SAH + OTN group received the OTN electroacupuncture treatment. For treatment with recombinant DKK1 (a Wnt/ß-catenin inhibitor), mice were injected with DKK1. Results: Our results found that OTN improved cognitive impairment and hippocampal neuron damage in SAH rats. Furthermore, OTN promoted the proliferation of neural stem cells in SAH rats. Mechanistically, OTN activated Wnt/ß-catenin signaling in SAH rats, as indicated by the increased expression levels of Wnt1, ß-Catenin, LMNB1, and p-GSK-3ß. DKK1 reversed the improvement effect of OTN on cognitive impairment and neuronal damage in SAH rats. Meanwhile, DKK1 blocked the promoting effect of OTN on the proliferation of NSCs in SAH rats. Conclusions: OTN electroacupuncture may be an effective therapeutic strategy for SAH.

The Role of the Orexin System in Craniocerebral Trauma-Induced Epilepsy in Mice.

BACKGROUND: Following traumatic brain injury (TBI), an imbalance arises in the central nervous system within the hippocampus region, resulting in the proliferation of mossy cell fibers, causing abnormal membrane discharge. Moreover, disruptions in cellular neurotransmitter secretion induce post-traumatic epilepsy. Extensive experimental and clinical data indicate that the orexin system plays a regulatory role in the hippocampal central nervous system, but the specific regulatory effects are unclear. Therefore, further experimental evaluation of its relevance is needed. OBJECTIVE: This study aims to investigate the effects of orexin receptor agonists (OXA) on the seizure threshold and intensity in controlled cortical impact (CCI) mice, and to understand the role of the orexin system in post-traumatic epilepsy (PTE). METHODS: Male C57BL/6 mice weighing 18-22 g were randomly divided into three groups: Sham, CCI, and CCI+OXA. The three groups of mice were sequentially constructed with models, implanted with electrodes, and established drug-delivery cannulas. After a 30-day recovery, the Sham and CCI groups were injected with physiological saline through the administration cannulas, while the CCI+OXA group was injected with OXA. Subsequently, all mice underwent electrical stimulation every 30 minutes for a total of 15 times. Epileptic susceptibility, duration, intensity, and cognitive changes were observed. Concurrently, the expression levels and changes of GABAergic neurons in the hippocampus of each group were examined by immunofluorescence. RESULTS: Injecting OXA into hippocampal CA1 reduces the threshold of post-traumatic seizures, prolongs the post-discharge duration, prolongs seizure duration, reduces cognitive ability, and exacerbates the loss of GABAergic neurons in the hippocampal region. CONCLUSIONS: Based on the results, we can find that injecting OXA antagonists into the CA1 region of the hippocampus can treat or prevent the occurrence and progression of post-traumatic epilepsy.

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.

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.

Endoplasmic Reticulum Stress Promotes Neuronal Damage in Neonatal Hypoxic-Ischemic Brain Damage by Inducing Ferroptosis.

Hypoxic-ischemic brain damage (HIBD) poses a significant risk of neurological damage in newborns. This study investigates the impact of endoplasmic reticulum stress (ERS) on neuronal damage in neonatal HIBD and its underlying mechanisms. HIBD neonatal rat model was constructed and pre-treated with 4-phenylbutiric acid (4-PBA). Nissl and TUNEL staining were utilised to assess neuronal damage and apoptosis in rat brains. HIBD cell model was established by inducing oxygen-glucose deprivation (OGD) in rat H19-7 neurons, which were then pre-treated with Thapsigargin (TG), Ferrostatin-1 (Fer-1), or both. Cell viability and apoptosis of H19-7 neurons were analysed using cell counting kit-8 assay and TUNEL staining. GRP78-PERK-CHOP pathway activity and glutathione peroxidase-4 (GPX4) expression in rat brains and H19-7 neurons were assessed using Western blot. Ferroptosis-related indicators, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and iron content, were measured using commercial kits in both rat brains and H19-7 neurons. GRP78-PERK-CHOP pathway was overactivated in HIBD neonatal rats' brains, which was mitigated by 4-PBA treatment. 4-PBA treatment demonstrated a reduction in neuronal damage and apoptosis in HIBD-affected neonatal rat brains. Furthermore, it attenuated ferroptosis in rats by increasing GPX4, GSH and SOD while decreasing MDA and iron content. In the OGD-induced H19-7 neurons, Fer-1 treatment counteracted the suppressive effects of TG on viability, the exacerbation of apoptosis, the promotion of ferroptosis and the activation of the GRP78-PERK-CHOP pathway. Overall, ERS facilitates neuronal damage in neonatal HIBD by inducing ferroptosis. Consequently, the suppression of ERS may represent a promising therapeutic strategy for treating neonatal HIBD.

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.