N-Acetylcysteine Attenuates Copper Overload-Induced Oxidative Injury in Brain of Rat

Copper is an integral part of many important enzymes involved in a number of vital biological processes. Even though it is essential to life, at elevated tissue concentrations, copper can become toxic to cells. Recent studies have reported oxidative damage due to copper in various tissues. Considering the vulnerability of the brain to oxidative stress, this study was undertaken to explore possible beneficial antioxidant effects of N-acetylcysteine on oxidative stress induced by copper overload in brain tissue of rats. Thirty-two Wistar rats were equally divided into four groups. The first group was used as control. The second, third, and fourth groups were given 1 g/L copper in their drinking water for 1 month. At the end of this period, the group 2 rats were sacrificed. During the next 2 weeks, the rats in group 3 were injected intraperitoneally with physiological saline and those in group 4 with 20 mg/kg intraperitoneal injections of N-acetylcysteine. In group 2 the lipid peroxidation and nitric oxide levels were increased in the brain cortex while the activities of superoxide dismutase and catalase and the concentration of glutathione were decreased. In rats treated with N-acetylcysteine, lipid peroxidation decreased and the activities of antioxidant enzyme improved in the brain cortex. In conclusion, treatment with N-acetylcysteine modulated the antioxidant redox system and reduced brain oxidative stress induced by copper.     

Etanercept Attenuates Myocardial Ischemia/Reperfusion Injury by Decreasing Inflammation and Oxidative Stress

The protective role of etanercept in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether etanercept modulates neutrophil accumulation, TNF-α induction and oxidative stress in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+ etanercept. The results demonstrated that compared to MI/R, etanercept reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels, and both serum and myocardial TNF-α production. Etanercept also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. In summary, our data suggested that etanercept has protective effects against MI/R injury in rats, which may be attributed to attenuating inflammation and oxidative stress.     

Systemic Evaluation of Hypoxic-Ischemic Brain Injury in Neonatal Rats

The objective of the study was to evaluate the systematically rat model of neonatal hypoxic-ischemic brain damage. The right carotid arteries of 7-day-old healthy Wistar rats were ligated, and then, the rats were subjected to an environment with 8 % of oxygen. Four weeks after the birth, neurobehavioral test, water maze test, and motor-evoked potential and neuropathologic examinations were performed. The footprint analysis showed significantly larger and instable paces in the hypoxic-ischemic group (P < 0.05); the time that rats crossed the balance beam in the hypoxic-ischemic group was longer than the control group (P < 0.05). The water maze test showed that the escape latency of hypoxic-ischemic group was significantly longer than that of control group (P < 0.05). The hindlimb quadriceps compound muscle-evoked potential CMEP of rats in hypoxic-ischemic group showed that the wave amplitude was lower than that of control group (P < 0.05). HE staining showed visible periventricular leukomalacia in hypoxic-ischemic groups; disrupted nuclear membrane was detected in the IH group with transelectronmicroscopy; Immunohistochemistry: compared with control group, MBP-positive neurocytes decreased, glial fibrillary acidic protein positive neurocytes increased in the periventricular zone (P < 0.05). Carotid artery ligation combining the hypoxic chamber created a reliable and stable rat model of neonatal hypoxic-ischemic brain damage and can be used for experimental research related to management of cerebral palsy.     

Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury

Neurochemical Research - Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor...     

AICAR Attenuates Organ Injury and Inflammatory Response after Intestinal Ischemia and Reperfusion

Intestinal ischemia and reperfusion (I/R) is encountered in various clinical conditions and contributes to multiorgan failure and mortality as high as 60% to 80%. Intestinal I/R not only injures the intestine, but affects remote organs such as the lung leading to acute lung injury. The development of novel and effective therapies for intestinal I/R are critical for the improvement of patient outcome. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) is a cell-permeable compound that has been shown to possess antiinflammatory effects. The objective is to determine that treatment with AICAR attenuates intestinal I/R injury and subsequent acute lung injury (ALI). Male Sprague Dawley rats (275 to 325 g) underwent intestinal I/R injury with blockage of the superior mesenteric artery for 90 min and subsequent reperfusion. At the initiation of reperfusion, vehicle or AICAR (30 mg/kg BW) was given intravenously (IV) for 30 min. At 4 h after reperfusion, blood and tissues were collected for further analyses. Treatment with AICAR significantly decreased the gut damage score and the water content, indicating improvement in histological integrity. The treatment also attenuated tissue injury and proinflammatory cytokines, and reduced bacterial translocation to the gut. AICAR administration after intestinal I/R maintained lung integrity, attenuated neutrophil chemotaxis and infiltration to the lungs and decreased lung levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Inflammatory mediators, lung-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, were decreased in the lungs and lung apoptosis was significantly reduced after AICAR treatment. These data indicate that AICAR could be developed as an effective and novel therapeutic for intestinal I/R and subsequent ALI.     

Plasticity of Neurons and Glia Following Neonatal Hypoxic-Ischemic Brain Injury in Rats

Periventricular white matter injury in premature infants is linked to chronic neurological dysfunction. Periventricular white matter injury is caused by many mechanisms including hypoxia-ischemia (HI). Animal models of HI in the neonatal rodent brain can replicate some important features of periventricular white matter injury. Most rodent studies have focused upon early cellular and tissue events following unilateral neonatal HI that is elicited by unilateral carotid artery ligation and followed by timed exposure to moderate hypoxia. Milder hypoxic-ischemic insults elicit preferential white matter injury. Little information is available about long-term cellular effects of unilateral HI. One month after unilateral neonatal hypoxia ischemia, we show that all the components for structural reorganization of the brain are present in moderately injured rats. These components in the injured side include extensive influx of neurites, axonal and dendritic growth cones, abundant immature synapses, and myelination of many small axons. Surprisingly, this neural recovery is often found in and adjacent to cysts that have the ultrastructural features of bone extracellular matrix. In contrast, brains with severe hypoxia ischemia one month after injury still undergo massive neuronal degeneration. While massive destruction of neurons and glia are striking events shortly after brain HI, neural cells re-express their intrinsic properties and attempt an anatomical recovery long after injury. Special issue dedicated to Anthony Campagnoni.     

Pterostilbene Attenuates Early Brain Injury Following Subarachnoid Hemorrhage via Inhibition of the NLRP3 Inflammasome and Nox2-Related Oxidative Stress

Pterostilbene (PTE), one of the polyphenols present in plants such as blueberries and grapes, has been suggested to have various effects, such as anti-oxidation, anti-apoptosis, and anti-cancer effects. Subarachnoid hemorrhage (SAH) is a severe neurological event known for its high morbidity and mortality. Recently, early brain injury (EBI) has been reported to play a significant role in the prognosis of patients with SAH. The present study aimed to investigate whether PTE could attenuate EBI after SAH was induced in C57BL/6 J mice. We also studied possible underlying mechanisms. After PTE treatment, the neurological score and brain water content of the mice were assessed. Oxidative stress and neuronal injury were also evaluated. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activity was assessed using western blot analysis. Our results indicated that PTE treatment reduces the SAH grade, neurological score, and brain water content following SAH. PTE treatment also reduced NLRP3 inflammasome activation. PTE alleviated the oxidative stress following SAH as evidenced by the dihydroethidium staining, superoxide dismutase activity, malondialdehyde content, 3-nitrotyrosie and 8-hydroxy-2-deoxyguanosine levels, and gp91^phox and 4-hydroxynonenal expression levels. Additionally, PTE treatment reduced neuronal apoptosis. In conclusion, our study suggests that PTE attenuates EBI following SAH possibly via the inhibition of NLRP3 inflammasome and Nox2-related oxidative stress.     

Resveratrol Attenuates Ischemia/Reperfusion Injury in Neonatal Cardiomyocytes and Its Underlying Mechanism

This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na⁺-K⁺-ATPase and Ca²⁺-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na⁺-K⁺-ATPase and Ca²⁺-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a K_ATP inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and K_ATP may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.     

Correction to: Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury

Neurochemical Research - The original version of this article unfortunately contained a mistake. The Fluorescence Immunoassays text written in Materials and Methods section and Fig.&nbsp;1i, j...     

Oxidative Injury in the Brain of mice Caused by Lanthanid

The organ toxicity of lanthanides (Ln) on organisms had been recognized, but very little is known about the oxidative injury of brain caused by Ln. In order to study the mechanisms underlying the effects of Ln on the brain, ICR mice were injected with a single 20 mg/kg body weight dose of LaCl₃, CeCl₃, and NdCl₃ into the abdominal cavity daily for 14 days. We then examined the coefficient of the brain, the brain pathological changes and oxidative stress-mediated responses, and the accumulation of Ln and levels of neurochemicals in the brain. The results showed that CeCl₃ and NdCl₃ could induce some neurons to turn inflammatory cells and slight edema but did not observe the brain pathological changes from LaCl₃-treated group. The concentrations of La, Ce, and Nd in the brain were significantly different and ranked in the order of Ce, Nd, and La. The injury of the brain and oxidative stress occurred as Ln appeared to trigger a cascade of reactions such as lipid peroxidation, the decreases of the total antioxidation capacity and activities of antioxidative enzymes, the excessive release of nitric oxide, the increase of glutamic acid, and the downregulated level of acetylcholinesterase activities. Furthermore, both Ce³⁺ and Nd³⁺ exhibited higher oxidative stress and toxicity on brain than La³⁺, and Ce³⁺ caused more severe brain injuries and oxidative stress than Nd³⁺, implying that the differences in the brain injuries caused by Ln might be related to the number of 4f electrons of Ln.     

Multi-Modal Assessment of Long-Term Erythropoietin Treatment after Neonatal Hypoxic-Ischemic Injury in Rat Brain

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.     

Nelfinavir Inhibits Intra-Mitochondrial Calcium Influx and Protects Brain against Hypoxic-Ischemic Injury in Neonatal Mice

Nelfinavir (NLF), an antiretroviral agent, preserves mitochondrial membranes integrity and protects mature brain against ischemic injury in rodents. Our study demonstrates that in neonatal mice NLF significantly limits mitochondrial calcium influx, the event associated with protection of the brain against hypoxic-ischemic insult (HI). Compared to the vehicle-treated mice, cerebral mitochondria from NLF-treated mice exhibited a significantly greater tolerance to the Ca²⁺-induced membrane permeabilization, greater ADP-phosphorylating activity and reduced cytochrome C release during reperfusion. Pre-treatment with NLF or Ruthenium red (RuR) significantly improved viability of murine hippocampal HT-22 cells, reduced Ca²⁺ content and preserved membrane potential (Ψm) in mitochondria following oxygen-glucose deprivation (OGD). Following histamine-stimulated Ca²⁺ release from endoplasmic reticulum, in contrast to the vehicle-treated cells, the cells treated with NLF or RuR also demonstrated reduced Ca²⁺ content in their mitochondria, the event associated with preserved Ψm. Because RuR inhibits mitochondrial Ca²⁺ uniporter, we tested whether the NLF acts via the mechanism similar to the RuR. However, in contrast to the RuR, in the experiment with direct interaction of these agents with mitochondria isolated from naïve mice, the NLF did not alter mitochondrial Ca²⁺ influx, and did not prevent Ca²⁺ induced collapse of the Ψm. These data strongly argues against interaction of NLF and mitochondrial Ca²⁺ uniporter. Although the exact mechanism remains unclear, our study is the first to show that NLF inhibits intramitochondrial Ca²⁺ flux and protects developing brain against HI-reperfusion injury. This novel action of NLF has important clinical implication, because it targets a fundamental mechanism of post-ischemic cell death: intramitochondrial Ca²⁺ overload → mitochondrial membrane permeabilization → secondary energy failure.     

Vagus Nerve Stimulation Attenuates Cerebral Ischemia and Reperfusion Injury via Endogenous Cholinergic Pathway in Rat

Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS) following focal cerebral ischemia and reperfusion (I/R) may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti-inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD) rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA), and immunofluorescence staining for the endogenous “cholinergic anti-inflammatory pathway” was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR), phosphorylated Akt (p-Akt), and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS) had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL) positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways.     

Neuroprotective Effects of Oligodendrocyte Progenitor Cell Transplantation in Premature Rat Brain following Hypoxic-Ischemic Injury

Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and -bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury.     

The Onset of Brain Injury and Neurodegeneration Triggers the Synthesis of Docosanoid Neuroprotective Signaling

Bioactive lipid messengers are formed through phospholipase-mediated cleavage of specific phospholipids from membrane reservoirs. Effectors that activate the synthesis of lipid messengers, include ion channels, neurotransmitters, membrane depolarization, cytokines, and neurotrophic factors. In turn, lipid messengers regulate and interact with multiple pathways, participating in the development, differentiation, function (e.g., long-term potentiation and memory), protection, and repair of cells of the nervous system. Overall, bioactive lipids participate in the regulation of synaptic function and dysfunction. Platelet-activating factor (PAF) and COX-2-synthesized PGE₂ modulate synaptic plasticity and memory. Oxidative stress disrupts lipid signaling, fosters lipid peroxidation, and initiates and propagates neurodegeneration. Lipid messengers participate in the interactions among neurons, astrocytes, oligodendrocytes, microglia, cells of the microvasculature, and other cells. A conglomerate of interrelated cells comprises the neurovascular unit. Signaling at the neurovascular unit is clearly altered in the early stages of cerebrovascular disease as well as in neurodegenerations. Here we will provide examples of how signaling by lipids regulates critical events essential for neuronal survival. We will highlight a newly identified, DHA-derived messenger, neuroprotectin D1, which attenuates oxidative stress-induced apoptosis. The specificity and potency of this novel docosanoid (neuroprotectin D1) indicate a potentially important target for therapeutic intervention.     

Echinacoside Alleviates Hypoxic-Ischemic Brain Injury in Neonatal Rat by Enhancing Antioxidant Capacity and Inhibiting Apoptosis

Hypoxic-ischemic brain damage (HIBD) is a leading cause of death and disability in neonatal or perinatal all over the world, seriously affecting children, families and society. Unfortunately, only few satisfactory therapeutic strategies have been developed. It has been demonstrated that Echinacoside (ECH), the major active component of Cistanches Herba, exerts many beneficial effects, including antioxidative, anti-apoptosis, and neuroprotective in the traditional medical practice in China. Previous research has demonstrated that ECH plays a protective effect on ischemic brain injury. This study aimed to investigate whether ECH provides neuroprotection against HIBD in neonatal rats. We subjected 120 seven-day-old Sprague–Dawley rats to cerebral hypoxia–ischemia (HI) and randomly divided into the following groups: sham group, HI group and ECH (40, 80 and 160 mg/kg, intraperitoneal) post-administration group. After 48 h of HI, 2,3,5-Triphenyltetrazolium chloride, Hematoxylin-Eosin and Nissl staining were conducted to evaluate the extent of brain damage. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, total antioxidant capacity (T-AOC), and malondialdehyde (MDA) production were assessed to determine the antioxidant capacity of ECH. TUNEL staining and Western blot analysis was performed to respectively estimate the extent of brain cell apoptosis and the expression level of the apoptosis-related proteins caspase-3, Bax, and Bcl-2. Results showed that ECH remarkably reduced the brain infarct volume and ameliorated the histopathological damage to neurons. ECH post-administration helped recovering the antioxidant enzyme activities and decreasing the MDA production. Furthermore, ECH treatment suppressed neuronal apoptosis in the rats with HIBD was by reduced TUNEL-positive neurons, the caspase-3 levels and increased the Bcl-2/Bax ratio. These results suggested that ECH treatment was beneficial to reducing neuronal damage by attenuating oxidative stress and apoptosis in the brain under HIBD.

     

Silencing of Long Noncoding RNA AK139328 Attenuates Ischemia/Reperfusion Injury in Mouse Livers

Recently, increasing evidences had suggested that long noncoding RNAs (LncRNAs) are involved in a wide range of physiological and pathophysiological processes. Here we determined the LncRNA expression profile using microarray technology in mouse livers after ischemia/reperfusion treatment. Seventy one LncRNAs were upregulated, and 27 LncRNAs were downregulated in ischemia/reperfusion-treated mouse livers. Eleven of the most significantly deregulated LncRNAs were further validated by quantitative PCR assays. Among the upregulated LncRNAs confirmed by quantitative PCR assays, AK139328 exhibited the highest expression level in normal mouse livers. siRNA-mediated knockdown of hepatic AK139328 decreased plasma aminotransferase activities, and reduced necrosis area in the livers with a decrease in caspase-3 activation after ischemia/reperfusion treatment. In ischemia/reperfusion liver, knockdown of AK139328 increased survival signaling proteins including phosphorylated Akt (pAkt), glycogen synthase kinase 3 (pGSK3) and endothelial nitric oxide synthase (peNOS). Furthermore, knockdown of AK139328 also reduced macrophage infitration and inhibited NF-κB activity and inflammatory cytokines expression. In conclusion, these findings revealed that deregulated LncRNAs are involved in liver ischemia/reperfusion injury. Silencing of AK139328 ameliorated ischemia/reperfusion injury in the liver with the activation of Akt signaling pathway and inhibition of NF-κB activity. LncRNA AK139328 might be a novel target for diagnosis and treatment of liver surgery or transplantation.     

The AMPAR Antagonist Perampanel Attenuates Traumatic Brain Injury Through Anti-Oxidative and Anti-Inflammatory Activity

Perampanel is a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of seizures. Recently, it was found to exert protective effects against ischemic neuronal injury in vitro. In the present study, we investigated the potential protective effects of perampanel in a traumatic brain injury (TBI) model in rats. Oral administration with perampanel at a dose of 5 mg/kg exerted no major organ-related toxicities. We found that perampanel significantly attenuated TBI-induced brain edema, brain contusion volume, and gross motor dysfunction. The results of Morris water maze test demonstrated that perampanel treatment also improved cognitive function after TBI. These neuroprotective effects were accompanied by reduced neuronal apoptosis, as evidenced by decreased TUNEL-positive cells in brain sections. Moreover, perampanel markedly inhibited lipid peroxidation and obviously preserved the endogenous antioxidant system after TBI. In addition, enzyme-linked immunosorbent assay (ELISA) was performed at 4 and 24 h after TBI to evaluate the expression of inflammatory cytokines. The results showed that perampanel suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1β, whereas increased the levels of anti-inflammatory cytokines IL-10 and TGF-β1. These data show that the orally active AMPAR antagonist perampanel affords protection against TBI-induced neuronal damage and neurological dysfunction through anti-oxidative and anti-inflammatory activity.