Extracorporeal cardiopulmonary resuscitation (ECPR) facilitates resuscitation with immediate and precise temperature control. This study aimed to determine the optimal reperfusion temperature to minimize neurological damage after ventricular fibrillation cardiac arrest (VFCA). Twenty-four rats were randomized (n = 8 per group) to normothermia (NT = 37°C), mild hypothermia (MH = 33°C) or moderate hypothermia (MOD = 27°C). The rats were subjected to 10 minutes of VFCA, before 15 minutes of ECPR at their respective target temperature. After ECPR weaning, rats in the MOD group were rapidly rewarmed to 33°C, and temperature maintained at 33°C (MH/MOD) or 37°C (NT) for 12 hours before slow rewarming to normothermia (MH/MOD). The primary outcome was 30-day survival with overall performance category (OPC) 1 or 2 (1 = normal, 2 = slight disability, 3 = severe disability, 4 = comatose, 5 = dead). Secondary outcomes included awakening rate (OPC ≤ 3) and neurological deficit score (NDS, from 0 = normal to 100 = brain dead). The survival rate did not differ between reperfusion temperatures (NT = 25%, MH = 63%, MOD = 38%, p = 0.301). MH had the lowest NDS (NT = 4[IQR 3-4], MH = 2[1-2], MOD = 5[3-5], p = 0.044) and highest awakening rate (NT = 25%, MH = 88%, MOD = 75%, p = 0.024). In conclusion, ECPR with 33°C reperfusion did not statistically significantly improve survival after VFCA when compared with 37°C or 27°C reperfusion but was neuroprotective as measured by awakening rate and neurological function.

Electroconvulsive therapy (ECT) is considered one of the most effective treatments for psychiatric disorders. ECT has proven effective in the treatment of depression, mania, catatonia and psychosis. It is presumed that seizures induced during ECT administration cause toxicity and potentially neuronal and glial cell death. A broad range of neurological disorders increase cerebrospinal fluid and serum levels of neuron-specific enolase (NSE) and S-100b protein. This study aims to investigate the effect of ECT on NSE and S-100b levels, which, together, serve as a proxy for neuronal cell damage. Serum concentrations of S-100b and NSE of adult patients who received ECT were measured by immunoluminometric analysis before and after treatment. A two-way ANOVA test was used to estimate the statistical differences in marker concentrations between the subgroups of the study population. Results: A total of 55 patients were included in the analysis: 52.73% (n = 29) were diagnosed with depression, 21.82% (n = 12) with schizophrenia or other psychosis, 16.36% (n = 9) with mania and 9.09% (n = 5) with catatonia. There were no statistically significant changes in NSE (p = 0.288) and S-100b (p = 0.243) levels. We found no evidence that ECT induced neuronal damage based on NSE and S-100b protein levels measured in the serum of patients before and after treatment.

BACKGROUND: Sevoflurane is a widely used inhalation anesthetic associated with neuronal damage, cognitive impairment and neurodegenerative diseases, with iron overload reported to contribute to these adverse effects. However, the mechanisms of iron-dependent cell death (ferroptosis) in sevoflurane-induced neurotoxicity remain poorly understood.
METHODS: The role of PLIN4, a protein associated with neurodegeneration, in sevoflurane-induced neuronal damage was investigated using cultured mouse hippocampal neurons (HT22). PLIN4 knockdown or overexpression was performed through vector transfection, and PLIN4 transcription and expression levels after sevoflurane treatment and knockdown experiments were assessed via RT-qPCR, immunostaining, and western blot to evaluate its impact on ferroptosis. Transmission electron microscopy was used to assess cellular morphology and measure Fe2+ levels.
RESULTS: Sevoflurane treatment significantly increased PLIN4 expression in hippocampal neurons and induced ferroptosis. Silencing PLIN4 reduced ferroptosis and partially reversed sevoflurane\'s inhibition of the Hippo signaling pathway. Specifically, sevoflurane treatment led to a 2.9-fold increase in PLIN4 mRNA levels. Furthermore, higher PLIN4 levels upregulated ferroptosis in hippocampal neurons by inhibiting the Hippo pathway.
CONCLUSIONS: Our study indicates that sevoflurane promotes ferroptosis in neurons by upregulating PLIN4 and modulating the Hippo signaling pathway. These findings provide insights into the potential development of interventions to prevent anesthesia-related cognitive impairments and neurodegeneration.

Alzheimer\'s disease (AD) is the most common cause of dementia and is caused by various factors including amyloid-beta (Aβ) aggregation. We investigated the pharmacological effects of the ethanol extract of Potentilla fragarioides var. major (Rosaceae) (EEPF) on AD-related pathogenesis, which remain elusive. We observed the effects of EEPF on Aβ disaggregation and free-radical scavenging activities for 2,2\'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) using in vitro assays, evaluated the effects of EEPF on memory loss in two animal models, and examined the molecular regulatory mechanisms of EEPF using an antibody-protein microarray in EEPF-treated neuronal cell lines. EEPF inhibited Aβ aggregation in a concentration-dependent manner and enhanced free-radical scavenging activities for ABTS and DPPH. EEPF significantly inhibited memory impairment in the passive avoidance task, Y-maze test, and Morris water maze test in scopolamine-induced short-term memory loss mice and Aβ-injected AD-like mice. Nissl staining and immunohistochemistry for NeuN and Iba-1 confirmed the neuroprotective and anti-inflammatory effects of EEPF in both animal models. In H2O2-treated HT22 hippocampal cells, EEPF significantly prevented cell damage, enhanced CaMK2, and reduced ferric reductase. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, EEPF significantly inhibited LPS-induced production of inflammatory factors, such as nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-6, and decreased the phosphorylation of Smad3 and cyclin D3. High-performance liquid chromatography confirmed that EEPF has five major components: neochlorogenic acid, chlorogenic acid, polydatin, isochlorogenic acid A, and buddleoside, with amounts ranging across 1.91-9.41 mg/g. EEPF may be a promising drug for treatment of AD and AD-related brain disorders.

Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC\'s capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC\'s therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC\'s neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.

UNASSIGNED: Neuroplasticity as a mechanism to overcome central nervous system injury resulting from different neurological diseases has gained increasing attention in recent years. However, deficiency of these repair mechanisms leads to the accumulation of neuronal damage and therefore long-term disability. To date, the mechanisms by which remyelination occurs and why the extent of remyelination differs interindividually between multiple sclerosis patients regardless of the disease course are unclear. A member of the neurotrophins family, the brain-derived neurotrophic factor (BDNF) has received particular attention in this context as it is thought to play a central role in remyelination and thus neuroplasticity, neuroprotection, and memory.
UNASSIGNED: To analyse the current literature regarding BDNF in different areas of multiple sclerosis and to provide an overview of the current state of knowledge in this field.
UNASSIGNED: To date, studies assessing the role of BDNF in patients with multiple sclerosis remain inconclusive. However, there is emerging evidence for a beneficial effect of BDNF in multiple sclerosis, as studies reporting positive effects on clinical as well as MRI characteristics outweighed studies assuming detrimental effects of BDNF. Furthermore, studies regarding the Val66Met polymorphism have not conclusively determined whether this is a protective or harmful factor in multiple sclerosis, but again most studies hypothesized a protective effect through modulation of BDNF secretion and anti-inflammatory effects with different effects in healthy controls and patients with multiple sclerosis, possibly due to the pro-inflammatory milieu in patients with multiple sclerosis. Further studies with larger cohorts and longitudinal follow-ups are needed to improve our understanding of the effects of BDNF in the central nervous system, especially in the context of multiple sclerosis.

OBJECTIVE: To detect possible neuronal damage due to recurrent isolated seizures in patients with epilepsy in a clinical routine setting.
METHODS: We measured the serum concentrations of neurofilament light chain (sNfL) in 46 outpatients with an at least monthly occurrence (self-reported) of generalized tonic-clonic seizures in the six months prior to the study and in 49 patients who had been seizure free (self-reported) for at least one year. We assigned the patients with seizure activity into groups with moderate and high seizure frequency. We measured sNfL with a highly sensitive single molecule array (Simoa).
RESULTS: The majority (94 %) of all patients with epilepsy had sNfL values within the age adjusted reference ranges of our laboratory. Three patients with and three patients without seizure activity (each 3 %) showed elevated sNfL concentrations. Age adjusted sNfL concentrations did not differ significantly between patients with and without seizure activity in the total sample or in the female subgroup. In contrast, NfL concentrations were significantly higher in male patients with seizure activity and highest in the subgroup of those with high seizure activity, but were only above the reference range in two patients. sNfL concentrations did not differ between focal and generalized epilepsies and between genetic and structural etiologies.
CONCLUSIONS: The sNfL concentrations in patients with epilepsy and healthy patients did not differ significantly. The finding of higher sNfL concentrations in males with self-reported seizure activity should be viewed with utmost caution because the difference was small and only two male patients showed sNfL concentrations above the reference range.

BACKGROUND: Hemorrhagic stroke is a devastating cerebrovascular event with a high rate of early mortality and long-term disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) for neurological conditions, such as intracerebral hemorrhage (ICH), has garnered considerable interest, has garnered considerable interest, though their mechanisms of action remain poorly understood.
METHODS: EVs were isolated from human umbilical cord MSCs, and SPECT/CT was used to track the 99mTc-labeled EVs in a mouse model of ICH. A series of comprehensive evaluations, including magnetic resonance imaging (MRI), histological study, RNA sequencing (RNA-Seq), or miRNA microarray, were performed to investigate the therapeutic action and mechanisms of MSC-EVs in both cellular and animal models of ICH.
RESULTS: Our findings show that intravenous injection of MSC-EVs exhibits a marked affinity for the ICH-affected brain regions and cortical neurons. EV infusion alleviates the pathological changes observed in MRI due to ICH and reduces damage to ipsilateral cortical neurons. RNA-Seq analysis reveals that EV treatment modulates key pathways involved in the neuronal system and metal ion transport in mice subjected to ICH. These data were supported by the attenuation of neuronal ferroptosis in neurons treated with Hemin and in ICH mice following EV therapy. Additionally, miRNA microarray analysis depicted the EV-miRNAs targeting genes associated with ferroptosis, and miR-214-3p was identified as a regulator of neuronal ferroptosis in the ICH cellular model.
CONCLUSIONS: MSC-EVs offer neuroprotective effects against ICH-induced neuronal damage by modulating ferroptosis highlighting their therapeutic potential for combating neuronal ferroptosis in brain disorders.

BACKGROUND: This work elucidated the effect of honokiol (HKL) on hippocampal neuronal mitochondrial function in Alzheimer\'s disease (AD).
METHODS: APP/PS1 mice were used as AD mice models and exposed to HKL and 3-TYP. Morris water maze experiment was performed to appraise cognitive performance of mice. Hippocampal Aβ+ plaque deposition and neuronal survival was evaluated by immunohistochemistry and Nissl staining. Hippocampal neurons were dissociated from C57BL/6 mouse embryos. Hippocampal neuronal AD model was constructed by Aβ oligomers induction and treated with HKL, CsA and 3-TYP. Neuronal viability and apoptosis were detected by cell counting kit-8 assay and TUNEL staining. mRFP-eGFP-LC3 assay, MitoSOX Red, dichlorodihydrofluorescein diacetate, and JC-1 staining were performed to monitor neuronal autophagosomes, mitochondrial reactive oxygen species (ROS), neuronal ROS, and mitochondrial membrane potential. Autophagy-related proteins were detected by Western blot.
RESULTS: In AD mice, HKL improved cognitive function, relieved hippocampal Aβ1-42 plaque deposition, promoted hippocampal neuron survival, and activated hippocampal SIRT3 expression and mitochondrial autophagy. These effects of HKL on AD mice were abolished by 3-TYP treatment. In hippocampal neuronal AD model, HKL increased neuronal activity, attenuated neuronal apoptosis and Aβ aggregation, activated SIRT3 and mitochondrial autophagy, reduced mitochondrial and neuronal ROS, and elevated mitochondrial membrane potential. CsA treatment and 3-TYP treatment abrogated the protection of HKL on hippocampal neuronal AD model. The promotion of mitochondrial autophagy by HKL in hippocampal neuronal AD model was counteracted by 3-TYP.
CONCLUSIONS: HKL activates SIRT3-mediated mitochondrial autophagy to mitigate hippocampal neuronal damage in AD. HKL may be effective in treating AD.

Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant mediators of cellular communication. The current study questioned the role of HSV-1-encoded and host-derived miRNAs in cerebrospinal fluid (CSF)-derived exosomes, enriched from stress-induced neuroinflammatory diseases, mainly subarachnoid hemorrhage (SAH), psychiatric disorders (AF and SZ), and various other neuroinflammatory diseases. The results were compared with CSF exosomes from control donors devoid of any neuroinflammatory pathology. Serology proved positive, but variable immunity against herpesviruses in the majority of patients, except controls. Selective ultrastructural examinations identified distinct, herpesvirus-like particles in CSF-derived lymphocytes and monocytes. The likely release of extracellular vesicles and exosomes was most frequently observed from CSF monocytes. The exosomes released were structurally similar to highly purified stem-cell-derived exosomes. Exosomal RNA was quantified for HSV-1-derived miR-H2-3p, miR-H3-3p, miR-H4-3p, miR-H4-5p, miR-H6-3p, miR-H27 and host-derived miR-21-5p, miR-146a-5p, miR-155-5p, and miR-138-5p and correlated with the oxidative stress chemokine IL-8 and the axonal damage marker neurofilament light chain (NfL). Replication-associated miR-H27 correlated with neuronal damage marker NfL, and cell-derived miR-155-5p correlated with oxidative stress marker IL-8. Elevated miR-138-5p targeting HSV-1 latency-associated ICP0 inversely correlated with lower HSV-1 antibodies in CSF. In summary, miR-H27 and miR-155-5p may constitute neuroinflammatory markers for delineating frequent and fluctuating HSV-1 replication and NfL-related axonal damage in addition to the oxidative stress cytokine IL-8 in the brain. Tentatively, HSV-1 remains a relevant pathogen conditioning autoimmune processes and a psychiatric clinical phenotype.