Neuronal Protective Effects Research Articles

Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit.

Metformin is one of the most commonly used oral hypoglycemic drugs in clinical practice, with unique roles in neurodegeneration and vascular lesions. Neurodegeneration and vasculopathy coexist in many diseases and typically affect the neurovascular unit (NVU), a minimal structural and functional unit in the central nervous system. Its components interact with one another and are indispensable for maintaining tissue homeostasis. This review focuses on retinal (diabetic retinopathy, retinitis pigmentosa) and cerebral (ischemic stroke, Alzheimer's disease) diseases to explore the effects of metformin on the NVU. Metformin has a preliminarily confirmed therapeutic effect on the retinal NUV, affecting many of its components, such as photoreceptors (cones and rods), microglia, ganglion, Müller, and vascular endothelial cells. Since it rapidly penetrates the blood-brain barrier (BBB) and accumulates in the brain, metformin also has an extensively studied neuronal protective effect in neuronal diseases. Its mechanism affects various NVU components, including pericytes, astrocytes, microglia, and vascular endothelial cells, mainly serving to protect the BBB. Regulating the inflammatory response in NVU (especially neurons and microglia) may be the main mechanism of metformin in improving central nervous system related diseases. Metformin may be a potential drug for treating diseases associated with NVU deterioration, however, more trials are needed to validate its timing, duration, dose, clinical effects, and side effects.

Evaluating the therapeutic effect of LIPUS in the early stage of traumatic brain injury using FA and T2* in rats.

To evaluate the protective effect of LIPUS at the early stage of brain trauma in rats, 45 rats were randomly divided into 3 groups: sham (n = 15), TBI (n = 15) and LIPUS treatment groups (n = 15). Ipsilateral and contralateral cortical and thalamic parameters obtained by diffusion tensor imaging (DTI) and fast low-angle shot magnetic resonance imaging (FLASH-MRI) were measured at different times after trauma. For fractional anisotropy (FA) and T2* values, two-way repeated measures ANOVA with Tukey's post hoc was used for intergroup comparisons. With observation time prolonged, the FA values of the ipsilateral cortex in the TBI group gradually increased and were significantly higher than those in the LIPUS treatment group on Day 7 (adjusted P = 0.0067). FA values in the contralateral cortex decreased at this time and were significantly lower than those in the LIPUS treatment group (adjusted P = 0.0192). Meanwhile, compared with LIPUS group, FA values were significantly higher in the injured thalamus (adjusted P = 0.0025). Combined with correlation analysis, FA values were positively correlated with neuronal damage (P = 0.0148, r2 = 0.895). At 7 days after trauma, T2* values in the ipsilateral cortex of the TBI group were significantly lower. After analysis of ferritin content and correlation, we found that T2* values were negatively correlated with ferritin (P = 0.0259, r2 = -0.849). By measuring post-traumatic changes in FA and T2* values, it is possible to demonstrate a neuronal protective effect of LIPUS in the early phase of TBI rats and promote brain rehabilitation.

Neuronal cell protective effects of phenolic compounds derived from steam exploded nematode-infected pine

Pine wilt disease is one of the most serious forest diseases that kills pine trees. Most of the nematode-infected pines are fumigated or locally incinerated and are thus not appropriately utilized. This study explored methods to utilize abandoned nematode-infected pines. The chemical compositions of healthy and nematode-infected pines were analyzed, and the neuroprotective effects of phenolic compounds extracted after steam explosion treatment were investigated. In terms of chemical composition, the nematode-infected pine chips suffered more damage from the steam explosion treatment than the healthy pine chips. In addition, the total phenolic compound content showed a clear difference depending on the presence of infection and steam explosion conditions. The maximum total phenolic compound content of extracted ethanol was found when the nematode-infected pine chip was subjected to steam explosion with a severity factor (Ro) of 3.82. The steam exploded pine extract of 10 μg/mL inhibited glutamate-induced early apoptotic cell death compared to cells treated with 10 mM glutamate alone. These results suggested that steam-exploded pine can be used as an effective natural material for neuronal cell protection.

Metabolomics analysis revealed the neuroprotective role of 2-phosphoglyceric acid in hypoxic-ischemic brain damage through GPX4/ACSL4 axis regulation

Hypoxic-ischemic brain damage (HIBD) is a cerebral injury resulting from the combination of ischemia and hypoxia in neonatal brain tissue. Presently, there exists no efficacious remedy for HIBD. A mounting body of evidence indicates that dynamic metabolites formed during metabolic procedures assume a vital role in neuronal maturation and recuperation. However, it remains unclear whether any endogenous metabolites are involved in the pathogenesis of HIBD. Here, an untargeted metabolomics analysis was conducted by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (GC/LC-MS) in OGD/R (oxygen-glucose deprivation/reoxygenation)-induced HT-22 cells. We observed that ferroptosis signaling plays an essential role in HI-induced neuronal injury. Interestingly, we also found that the differentially expressed metabolite, 2-phosphoglyceric acid, significantly improved the neuronal cell survival of OGD/R HT-22 cells by inhibiting ferroptosis. Moreover, 2-phosphoglyceric acid effectively rescued the cell activity of HT-22 cells treated with the ferroptosis inducer RSL-3. Furthermore, 2-phosphoglyceric acid alleviated cerebral infarction and reduced HIBD-induced neuronal cell loss of the central nervous system in neonatal rats by regulating GPX4 expression. Taken together, we found that 2-phosphoglyceric acid, which was downregulated in HT-22 cells induced by OGD/R, exerted neuronal protective effects on OGD/R-treated HT-22 cells and HIBD-induced neonatal rats by inhibiting hypoxic-ischemic-induced ferroptosis through the regulation of the GPX4/ACSL4 axis.

Coffee and Alzheimer's disease.

Coffee, a universally consumed beverage, is known to contain thousands of bioactive constituents that have garnered interest due to their potential neuroprotective effects against various neurodegenerative disorders, including Alzheimer's disease (AD). Extensive research has been conducted on coffee constituents such as Caffeine, Trigonelline, Chlorogenic acid, and Caffeic acid, focusing on their neuroprotective properties. These compounds have potential to impact key mechanisms in AD development, including amyloidopathy, tauopathy, and neuroinflammation. Furthermore, apart from its neuroprotective effects, coffee consumption has been associated with anticancerogenic and anti-inflammatory effects, thereby enhancing its therapeutic potential. Studies suggest that moderate coffee intake, typically around two to three cups daily, could potentially contribute to mitigating AD progression and lowering the risk of related neurological disorders. This literature underscores the potential neuroprotective properties of coffee compounds, which usually perform their neuronal protective effects via modulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor erythroid-derived 2-like 2 (Nrf2), interleukins, tumor necrosis factor-alpha (TNF-α), and many other molecules.

Electroacupuncture improves cognitive function in APP/PS1 mice by inhibiting oxidative stress related hippocampal neuronal ferroptosis

BackgroundElectroacupuncture, recognized as a crucial non-pharmacological therapeutic approach, has demonstrated notable efficacy in enhancing cognitive function among Alzheimer's disease (AD) patients. This study aimed to investigate the neuroprotective properties of electroacupuncture in APP/PS1 mice with AD. MethodsA total of thirty APP/PS1 mice were randomly assigned to three groups: the Alzheimer's disease group (AD), the electroacupuncture treatment group (EA), and the ferroptosis inhibitor deferasirox treatment group (DFX). Additionally, ten C57BL/6 mice were included as a control group (Control). In the EA group, mice underwent flat needling at Baihui and Yintang, as well as point needling at Renzhong, once daily for 15 min each time. In the DFX group, mice received intraperitoneal injections of deferasirox at a dosage of 100 mg/kg/day. Following the 28-day treatment period, behavioral evaluation, morphological observation of neurons, and detection of neuronal ferroptosis were conducted. ResultsThe electroacupuncture treatment demonstrated a significant improvement in spatial learning, memory ability, and neuronal damage in mice with AD. Analysis of neuronal ferroptosis markers indicated that electroacupuncture interventions reduced the elevated levels of malondialdehyde, iron, and ptgs2 expression, while also increasing superoxide dismutase activity, Ferroportin 1 and glutathione peroxidase 4 expression. Moreover, the regulatory impact of electroacupuncture on ferroptosis may be attributed to its ability to enhance the expression and nuclear translocation of Nrf2. ConclusionsThis study suggested that electroacupuncture could inhibit the neuronal ferroptosis by activating the antioxidant function in neurons through p62/Keap1/Nrf2 signal pathway, thereby improve the cognitive function of AD mice by the neuronal protection effect.

Neuronal Protective Effect of Nosustrophine in Cell Culture Models

Neuronal Protective Effect of Nosustrophine in Cell Culture Models

Abstract 15835: Inhibition of Soluble Epoxide Hydrolase Reduces Cognitive Impairment and Improves Cerebral Hemodynamics in AD/ADRD

Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD) is an emerging global healthcare crisis. However, underlying mechanisms have not been understood well enough to translate into precision medicine. Recent human genetic evidence indicated that soluble hydrolase (sEH) is linked to AD/ADRD. Inhibition of sEH has been reported to improve cognition in AD mice due to its anti-inflammatory and neuronal protective effects. Here, we examined whether inhibition of sEH with TPPU could reduce cognitive impairments by improving cerebral hemodynamics in 18-month-old diabetes (DM)-related ADRD rats and 6 months of TgF344-AD rats. The myogenic responses of the middle cerebral artery (MCA) were impaired in both AD and ADRD rats and were normalized with TPPU. The inner diameters of MCA increased by 49.16 ± 17.02 % in DM rats but decreased by 16.06 ± 2.46% and 11.24 ± 0.05% in age-matched control and TPPU-treated DM rats when pressure was elevated from 40 to 180 mmHg. Similarly, TPPU-treated AD rats significantly enhanced the MCA constriction by 25%. Forced dilatation occurred at pressures > 140 mmHg in MCAs in both rats and was rescued with TPPU treatment. Endothelial denuded MCAs from TPPU-treated DM rats constricted to 75.15 ± 4.25 % at a perfusion pressure of 140 mmHg and further constricted to 74.66 ± 4.01 % at 180 mmHg, compared to dilation of 155.48 ± 17.35 % and 172.78 ± 13.36 % in DM rats at the same pressures. The percentage of time spent with the novel object was 43.32 ± 8.04% and 83.23 ± 8.70% in DM and TPPU-treated DM rats, versus 75.68 ± 3.33% in non-DM rats. Impaired learning and short and long-term memory function examined with an 8-arm water maze in both DM and AD rats were rescued with TPPU treatment. These results provide the first evidence demonstrating that inhibition of sEH reverses cerebrovascular dysfunction and cognitive impairments in AD/ADRD.

Effect of intranasal and oral administration of levetiracetam onthe temporal and spatial distributions of SV2A in the KA-induced rat model of SE.

To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra-amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.

Microglial SIRT1 activation attenuates synapse loss in retinal inner plexiform layer via mTORC1 inhibition

BackgroundOptic nerve injury (ONI) is a key cause of irreversible blindness and triggers retinal ganglion cells (RGCs) change and synapse loss. Microglia is the resistant immune cell in brain and retina and has been demonstrated to be highly related with neuron and synapse injury. However, the function of Sirtuin 1 (SIRT1), a neuroprotective molecule, in mediating microglial activation, retinal synapse loss and subsequent retinal ganglion cells death in optic nerve injury model as well as the regulatory mechanism remain unclear.MethodTo this end, optic nerve crush (ONC) model was conducted to mimic optic nerve injury. Resveratrol and EX527, highly specific activator and inhibitor of SIRT1, respectively, were used to explore the function of SIRT1 in vivo and vitro. Cx3Cr1-CreERT2/RaptorF/F mice were used to delete Raptor for inhibiting mammalian target of rapamycin complex 1 (mTORC1) activity in microglia. HEK293 and BV2 cells were transfected with plasmids to explore the regulatory mechanism of SIRT1.ResultsWe discovered that microglial activation and synapse loss in retinal inner plexiform layer (IPL) occurred after optic nerve crush, with later-development retinal ganglion cells death. SIRT1 activation induced by resveratrol inhibited microglial activation and attenuated synapse loss and retinal ganglion cells injury. After injury, microglial phagocytosed synapse and SIRT1 inhibited this process to protect synapse and retinal ganglion cells. Moreover, SIRT1 exhibited neuron protective effects via activating tuberous sclerosis complex 2 (TSC2) through deacetylation, and enhancing the inhibition effect of tuberous sclerosis complex 2 on mammalian target of rapamycin complex 1 activity.ConclusionOur research provides novel insights into microglial SIRT1 in optic nerve injury and suggests a potential strategy for neuroprotective treatment of optic nerve injury disease.

Capsaicin, The Vanilloid Receptor TRPV1 Agonist in Neuroprotection: Mechanisms Involved and Significance.

Hot peppers, also called chilli, chilli pepper, or paprika of the plant genus Capsicum (family Solanaceae), are one of the most used vegetables and spices worldwide. Capsaicin (8-methyl N-vanillyl-6-noneamide) is the main pungent principle of hot green and red peppers. By acting on the capsaicin receptor or transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1), capsaicin selectively stimulates and in high doses defunctionalizes capsaicin-sensitive chemonociceptors with C and Aδ afferent fibers. This channel, which is involved in a wide range of neuronal processes, is expressed in peripheral and central branches of capsaicin-sensitive nociceptive neurons, sensory ganglia, the spinal cord, and different brain regions in neuronal cell bodies, dendrites, astrocytes, and pericytes. Several experimental and clinical studies provided evidence that capsaicin protected against ischaemic or excitotoxic cerebral neuronal injury and may lower the risk of cerebral stroke. By preventing neuronal death, memory impairment and inhibiting the amyloidogenic process, capsaicin may also be beneficial in neurodegenerative disorders such as Parkinson's or Alzheimer's diseases. Capsaicin given in systemic inflammation/sepsis exerted beneficial antioxidant and anti-inflammatory effects while defunctionalization of capsaicin-sensitive vagal afferents has been demonstrated to increase brain oxidative stress. Capsaicin may act in the periphery via the vagal sensory fibers expressing TRPV1 receptors to reduce immune oxidative and inflammatory signalling to the brain. Capsaicin given in small doses has also been reported to inhibit the experimentally-induced epileptic seizures. The aim of this review is to provide a concise account on the most recent findings related to this topic. We attempted to delineate such mechanisms by which capsaicin exerts its neuronal protective effects. We also aimed to provide the reader with the current knowledge on the mechanism of action of capsaicin on sensory receptors.

Neuroprotective Effects of Activin A against Cerebral Ischemia/Reperfusion Injury in Mice by Enhancing Nrf2 Expression to Attenuate Neuronal Ferroptosis.

Activin A (Act A) is a member of the transforming growth factor-β (TGF-β) superfamily and can protect against ischemic cerebral injury. Ferroptosis, a newly discovered type of programmed cell death, contributes to the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). However, little is known on whether Act A can modulate neuronal ferroptosis to protect against CIRI in a mouse model of middle cerebral artery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The results indicated that Act A treatment relieved CIRI by improving neurological deficits and reducing the infarct volume in mice. MCAO stimulated iron accumulation and malondialdehyde formation and upregulated ACSL4 expression but downregulated GPX4 expression, a hallmark of ferroptosis in the brain of mice. Treatment with Act A significantly mitigated MCAO-triggered ferroptosis in the brain of mice. Furthermore, Act A treatment enhanced the MCAO-upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression in the brains of mice. Similar results were observed in HT22 cells following OGD/R and pretreatment with Act A. The neuronal protective effect of Act A in HT22 cells was attenuated by treatment with ML385, an Nrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2 expression and inhibiting neuronal ferroptosis.

Neuronal Protective Effect of Nosustrophine in Cell Culture Models

Neuronal Protective Effect of Nosustrophine in Cell Culture Models

Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 μM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1β, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg-1·d-1, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

Paeoniflorin improves cognitive dysfunction, restores glutamate receptors, attenuates gliosis and maintains synaptic plasticity in cadmium-intoxicated mice

Toxic metals exposed to the environment in industrial and agricultural production, such as cadmium (Cd), Plumbum (Pb) and aluminium (Al), are neurotoxic and harmful to brain functions such as learning and memory, and may contribute to neurological disease. In this study, we investigated the neuronal protective effects of Paeoniflorin (PF) in a mouse model of Cd poisoning that showed cognitive dysfunction. PF attenuated Cd-induced multi-organ damage and brain neurotoxicity, consistent with improved behavioral performances in mice. At the molecular level, Cd-induced toxicity attenuated the phosphorylation of glutamate receptors NMDAR2A, NMDAR2B, and GluR2, but increased the phosphorylation of GluR1. In addition, gliosis after Cd toxicity showed an increase in the number of IBA1 or GFAP-positive cells, which contrasted with the loss of neurons and synapses. However, PF treatment alleviated gliosis and maintained glutamate receptor and neuronal activity, as evidenced by the recovery of marker proteins MAP2, PSD95 and synaptophysin. Also, Cd-induced upregulation of CD68, a lysosomal protein that scavenges damaged cellular components in active microglia, was also restored by PF. In conclusion, PF is a potential neuroprotective natural product.

The AMPK-SIRT1-FoxO1-NF-κB signaling pathway participates in hesperetin-mediated neuroprotective effects against traumatic brain injury via the NLRP3 inflammasome

Background Traumatic brain injury (TBI) induces inflammations that lead to secondary damage. Hesperetin (Hes) exerts anti-inflammatory activities against central nervous system (CNS) diseases. This article probes the possible neuroprotective effect and mechanism of Hes on TBI-induced acute cerebral damage. Methods Male C57BL/6J mice were subjected to controlled cortical impingement (CCI) and Hes (50 mg/kg) treatment after the surgery. Short-term neurological deficits were assessed with the modified neurological severity score (mNSS) and the Rota-rod test. The brain edema was tested by the wet/dry method. Neuron apoptosis was evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The blood-brain barrier (BBB) integrity was measured by Evans’ blue staining, and immunohistochemistry (IHC) was conducted to study BV2 microglial activation. BV2 microglia and HT22 neuronal cells were stimulated by oxygen-glucose deprivation followed by recovery (OGD/R) and processed with Hes. Quantitative real-time-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were implemented to gauge the expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-β (IL-1-β) and interleukin-6 (IL-6). Western blot (WB) was performed to check AMPK-SIRT1-FoxO1 both in vitro and in vivo. Results Hes eased neurological deficits, cerebral edema, and neuronal apoptosis in mice following TBI. Hes hampered microglial activation and pro-inflammatory cytokines production. Hes promoted AMPK and SIRT1 expression, whereas repressed the phosphorylation of FoxO1-NF-κB, and inhibited NLRP3 expression. The AMPK inhibitor Compound C markedly reversed Hes-mediated anti-inflammatory and neuron-protective effects. Conclusion Hes curbs microglial activation-mediated inflammation via the AMPK-SIRT1-FoxO1-NF-κB axis, thereby improving neurobehavioral function after TBI.

PO021 / #462 TRANSAURICULAR VAGAL NERVE STIMULATION AT 40HZ HAS NEURON-PROTECTIVE EFFECTS IN BOTH C57BL/6 MICE AND APP/PS1 MICE: E-POSTER VIEWING

Multi-sensory gamma (40Hz) stimulation ameliorates Alzheimer's-associated pathology. It is uncertain whether transauricular vagal nerve stimulation (taVNS) at 40Hz has the same effect. Thus, this study was designed to investigate whether 40Hz-taVNS has neuron-protective effects.

Peroxiredoxin 2 Ameliorates AβO-Mediated Autophagy by Inhibiting ROS via the ROS-NRF2-p62 Pathway in N2a-APP Swedish Cells.

In Alzheimer’s disease, reactive oxygen species (ROS) are generated by the deposition of amyloid-beta oligomers (AβOs), which represent one of the important causes of neuronal cell death. Additionally, AβOs are known to induce autophagy via ROS induction. Previous studies have shown that autophagy upregulation aggravates neuronal cell death. In this study, the effects of peroxiredoxin 2 (Prx2), a member of the peroxidase family of antioxidant enzymes, on regulating AβO-mediated autophagy were investigated. Prx2 decreased AβO-mediated oxidative stress and autophagy in N2a-APPswe cells. Further, we examined the relationship between the neuronal protective effect of Prx2 and a decrease in autophagy. Similar to the effects of N-acetyl cysteine, Prx2 decreased AβO-induced ROS and inhibited p62 protein expression levels by downregulating the activation of NRF2 and its translocation to the nucleus. In addition, treatment with 3-methyladenine, an autophagy inhibitor, ameliorates neuronal cell death. Overall, these results demonstrate that the Prx2-induced decrease in autophagy was associated with the inhibition of ROS via the ROS–NRF2–p62 pathway in N2a-APPswe cells. Therefore, our results revealed that Prx2 is a potential therapeutic target in anti-Alzheimer therapy.

Steroid Receptor Coactivator-Interacting Protein (SIP) Alleviates Ischemic Cerebral Infarction Damage Through the NF-κB Pathway.

Ischemic stroke leads to high mortality and disability rates in humans. Cerebral ischemic injury has a severe complex pathophysiological mechanism. The abnormal release of inflammatory cytokines will cause brain tissue damage and destroy the blood-brain barrier integrity, which aggravates the process of brain injury. Therefore, attenuating the level of inflammatory response is critical for the therapy of cerebral ischemia injury. This study examined the rule of SIP treatment to support neuron protective effect after cerebral injury in an animal model of middle cerebral artery occlusion (MCAO). After ischemia/reperfusion, neurological function, neuroglia cells activation, infarction volume, brain water content, brain tissue apoptosis ratio, and inflammatory response were assessed, and quantitative PCR and western blot were also detected, respectively. Treatment of SIP ameliorated neurological dysfunction, brain infarction, brain edema, and brain cell apoptosis after MCAO operation. Overexpression SIP also suppressed pro-inflammatory cytokines release. Furthermore, the protective effect of SIP on brain injury occurs through reduced neuroglia cells activation through downregulation of the NF-κB pathway. In summary, the present work indicated that SIP prevents ischemic cerebral infarction-induced inflammation and apoptosis by blocking inflammasome activation via NF-κB signaling pathway. Those results suggest that SIP treatment is an attractive strategy for prevention of ischemic cerebral infarction.

Anti-Seizure and Neuronal Protective Effects of Irisin in Kainic Acid-Induced Chronic Epilepsy Model with Spontaneous Seizures.

An increased level of reactive oxygen species is a key factor in neuronal apoptosis and epileptic seizures. Irisin reportedly attenuates the apoptosis and injury induced by oxidative stress. Therefore, we evaluated the effects of exogenous irisin in a kainic acid (KA)-induced chronic spontaneous epilepsy rat model. The results indicated that exogenous irisin significantly attenuated the KA-induced neuronal injury, learning and memory defects, and seizures. Irisin treatment also increased the levels of brain-derived neurotrophic factor (BDNF) and uncoupling protein 2 (UCP2), which were initially reduced following KA administration. Furthermore, the specific inhibitor of UCP2 (genipin) was administered to evaluate the possible protective mechanism of irisin. The reduced apoptosis, neurodegeneration, and spontaneous seizures in rats treated with irisin were significantly reversed by genipin administration. Our findings indicated that neuronal injury in KA-induced chronic epilepsy might be related to reduced levels of BDNF and UCP2. Moreover, our results confirmed the inhibition of neuronal injury and epileptic seizures by exogenous irisin. The protective effects of irisin may be mediated through the BDNF-mediated UCP2 level. Our results thus highlight irisin as a valuable therapeutic strategy against neuronal injury and epileptic seizures.