Hydroalcoholic extract of Zizyphus jujuba ameliorates seizures, oxidative stress, and cognitive impairment in experimental models of epilepsy in rats

The anticonvulsant effect of the hydroalcoholic extract of Zizyphus jujuba (HEZJ) fruit (100, 250, 500, and 1000 mg/kg, orally) was evaluated in experimental seizure models in rats. The effect of HEZJ on seizure-induced cognitive impairment, oxidative stress, and cholinesterase activity was also investigated. HEZJ (1000 mg/kg) exhibited maximum protection (100%) against generalized tonic-clonic seizures in the pentylenetetrazole (PTZ) seizure model and and 66.7% protection against tonic hindlimb extension in the maximal electroshock (MES) seizure model. Significant impairment in cognitive functions was observed in both PTZ- and MES-challenged rats. Pretreatment with HEZJ resulted in significant improvement in learning and memory. HEZJ also reversed the oxidative stress induced by both PTZ and MES. The significant decrease in cholinesterase activity observed in the PTZ and MES models was significantly reversed by pretreatment with HEZJ. Thus, the present study demonstrates the anticonvulsant effect of HEZJ as well as amelioration of cognitive impairment induced by seizures in rats.     

Root extract of Anacyclus pyrethrum ameliorates seizures, seizure-induced oxidative stress and cognitive impairment in experimental animals

In Ayurveda, Anacyclus pyrethrum has been used as a brain tonic. The present study evaluates the effect of hydroalcoholic extract of A. pyrethrum (HEAP) root against seizures, seizure-induced oxidative stress and cognitive impairment in experimental models of seizures. Male Wistar rats were used in the study. HEAP was administered in doses of 50, 100, 250, 500 in pentylenetetrazole (PTZ) model and 250, 500 and 1000 mg/kg in maximal electroshock (MES) model. Myoclonic jerk latency and generalized tonic clonic seizures (GTCS) were noted in PTZ whereas occurrence of tonic hind limb extension (THLE) was observed in MES seizures. Cognitive deficit was assessed using elevated plus maze and passive avoidance tests. Whole brain reduced glutathione, malondialdehyde levels and cholinesterase activity were measured. HEAP showed 50, 66.7, 83.3 and 100% protection at 50,100, 250 and 500 mg/kg, respectively against GTCS in PTZ induced seizures. In MES induced seizures, HEAP produced 16.7, 33.3 and 50% protection against THLE at 250, 500 and 1000 mg/kg, respectively. HEAP administration significantly prevented seizure induced oxidative stress and cognitive impairment in a dose-dependent manner. HEAP also normalized the decrease in cholinesterase activity caused by seizures. Thus, HEAP showed protective effect against seizures, seizure-induced oxidative stress and cognitive impairment in rats.     

Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress

Conventional antiepileptic drugs fail to adequately control seizures and predispose to cognitive impairment and oxidative stress with chronic usage in a significant proportion of patients with epilepsy. Coenzyme Q10 (CoQ10), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. To evaluate the neuroprotective effects of CoQ10 in rats against the observed oxidative stress during seizures induced by pilocarpine, and to study its interactions with the conventional antiepileptic drug phenytoin, two experiments were performed. Experiment 1 was conducted to test the effect of phenytoin, CoQ10, or both on seizure severity and oxidative markers in the pilocarpine model of epilepsy. Experiment 2 was conducted to test the effect of 2 weeks of chronic treatment with phenytoin, CoQ10, or both on oxidative markers and behavioral tests in rats. Overall, CoQ10 reduced the severity of pilocarpine-induced seizures and the severity of oxidative stress. Moreover, it potentiated the antiepileptic effects afforded by phenytoin treatment, with the potential safety and efficacy in ameliorating oxidative stress and cognitive impairment caused by chronic phenytoin therapy. Our findings strongly suggest that CoQ10 can be considered a safe and effective adjuvant to phenytoin therapy in epilepsy both to ameliorate seizure severity and to protect against seizure-induced oxidative damage by reducing the cognitive impairment and oxidative stress associated with chronic use of phenytoin.     

Aminoguanidine alleviated MMA-induced impairment of cognitive ability in rats by downregulating oxidative stress and inflammatory reaction

Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many “treated” patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment.     

Hydroxycitric acid ameliorates inflammation and oxidative stress in mouse models of multiple sclerosis

Hydroxycitric acid(HCA) is derived primarily from the Garcinia plant and is widely used for its anti-inflammatory effects. Multiple sclerosis can cause an inflammatory demyelination and axonal damage. In this study, to validate the hypothesis that HCA exhibits therapeutic effects on multiple sclerosis, we established female C57BL/6 mouse models of multiple sclerosis, i.e., experimental autoimmune encephalomyelitis,using Complete Freund's Adjuvant(CFA) emulsion containing myelin oligodendrocyte glycoprotein(35–55). Treatment with HCA at 2 g/kg/d for 3 weeks obviously improved the symptoms of nerve injury of experimental autoimmune encephalomyelitis mice, decreased serum interleulin-6, tumor necrosis factor alpha, nitric oxide, and malondialdehyde levels, and increased superoxide dismutase and glutathione reductase activities. These findings suggest that HCA exhibits neuroprotective effects on multiple sclerosis-caused nerve injury through ameliorating inflammation and oxidative stress.     

Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis‐associated encephalopathy

BackgroundFisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis‐associated encephalopathy (SAE) remains unclarified.MethodsCecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood‐brain barrier (BBB) integrity was detected by Evan''s blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro‐inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes.ResultsRats in the CLP group presented increased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase‐1 expression and IL‐1β secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase‐1 and reduced release of IL‐1β into CNS.ConclusionCollectively, fisetin‐blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL‐1β into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.     

Possible role of diabetes and related mechanisms in COVID-19-induced cognitive impairment

European Archives of Psychiatry and Clinical Neuroscience -     

Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease

Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.     

美满霉素改善血管性痴呆大鼠认知功能损伤并抑制氧化应激

目的 观察美满霉素(minocycline)对血管性痴呆大鼠学习记忆功能和脑组织内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)表达的影响,探讨美满霉素对血管性痴呆的脑保护作用的机制.方法 Wistar大鼠随机分为假手术组(S组)、痴呆模型组(M组)、美满霉素治疗组(MT组).RT-PCR和免疫组织化学法检测大鼠脑组织eNOS、iNOS的表达,行为学检测大鼠学习记忆功能的改变.结果 M组与S组行为学检查显示,M组大鼠有显著学习记忆障碍(P＜0.01),MT组与M组比较行为学检测结果显示,MT组大鼠学习记忆障碍有显著改善(P＜0.01).MT组iNOS表达较M组降低(P＜0.01),MT组eNOS表达较M组增高(P＜0.05);MT组eNOS、iNOS表达较S组增高(P＜0.01);M组eNOS、iNOS表达较S组显著增高(P＜0.01).结论 美满霉素能降低血管性痴呆大鼠脑组织iNOS表达,增强eNOS表达,抑制氧化应激反应,发挥脑保护作用.     

Cerebral hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative stress

Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of cognitive impairment in the elderly. In the pathogenesis of cognitive impairment, the association of neurodegenerative and vascular factors indicates a major role of hemodynamic abnormalities including cerebral hypoperfusion. There is also ample evidence that oxidative stress of vascular origin leads to profound alterations in cerebrovascular regulation and is crucial to cerebrovascular dysfunction in a variety of conditions that result in chronic hypoperfusion of the brain. In rodents, experimental chronic cerebral hypoperfusion (CCH) can be initiated by occlusion of the major arterial supply. This way CCH brings about mitochondrial dysfunction and protein synthesis inhibition. These effects may destroy the balance of antioxidases and reactive oxygen species (ROS) and produce oxidative damage. At the same time, oxidative injury to vascular endothelial cell, glia, and neuron impairs vascular function and neurovascular coupling, which may result in a vicious cycle of further reduction of cerebral perfusion. In clinical cases of severe cognitive dysfunction, vascular risk factors are commonly present, while cerebral hypoperfusion is often associated with vascular oxidative damage. Thus we hypothesize that cerebral hypoperfusion is one of the key factors in the development of cognitive impairment, in which vascular oxidative stress plays a major role. The approaches against cerebrovascular dysfunction, combined with antioxidants and others, might make a promising contribution to the treatment of cognitive impairment.     

Mild cognitive impairment: pathology and mechanisms

Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follow a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well-characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases who died with a clinical diagnosis of MCI. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular, biochemical and molecular deficits, many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI suggests that there is no single event which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drives cognitive decline as a final common pathway at this stage of the dementing disease process.     

Decreased cerebral perfusion and oxidative stress result in acute and delayed cognitive impairment

Chronic cerebral hypoperfusion (CCH) is common in the pathogenesis of cognitive impairment, in which oxidative stress plays an important role. Here we describe an alternative rat model for CCH that involves two-stage, three-vessel occlusion (2s-3VO) and compare its effects with those of permanent bilateral occlusion (2VO) of the common carotid arteries. Real-time cerebral blood flow (CBF) during the surgery was monitored. Spatial learning and memory were tested with the Morris water maze, and oxidative damage was evaluated by measuring malondialdehyde (MDA) levels in both the hippocampus and cortex. We found that the CBF drop in the early stage of the 2s-3VO model was more modest than that in the 2VO model. Like 2VO rats, 2s-3VO rats showed impaired spatial learning and memory and increased MDA levels 8 weeks after surgery. Interestingly, when pooling observations from previous studies, we confirmed that oxidative damage appeared later than spatial learning and memory deficits but lasted longer than did cerebral hypoperfusion. Thus, the 2s-3VO model appears to be a suitable model for the study of CCH. Moreover, data support the notion that cognitive impairment in CCH rat models may be induced early by cerebral hypoperfusion early and in a later phase by oxidative stress.     

Effects of carbamazepine on bicuculline- and pentylenetetrazol-induced seizures in developing rats.

The anticonvulsant effect of carbamazepine (CBZ) was examined in 10-, 18- and 25-day-old Wistar albino rats into which bicuculline or pentylenetetrazol had been systemically injected to induce generalized epileptic manifestations typical for the specific age of the animals. The results showed that: a) in developing rats, CBZ appears to be more effective in the pentylenetetrazol than the bicuculline model of epilepsy; b) in both models of epilepsy the efficacy of CBZ increases with the age of the animals; and c) among the various epileptic manifestations, the tonic phase is the most sensitive to the anticonvulsant effect of CBZ. These conclusions are correlated with the different levels of cerebral maturation of the animals, and are discussed with reference to the mechanisms of action of CBZ and bicuculline or pentylenetetrazol.     

Prevalence,mechanisms, and management of cancer-related cognitive impairment

Abstract

This review summarizes the current literature on cancer-related cognitive impairment (CRCI) with a focus on prevalence, mechanisms, and possible interventions for CRCI in those who receive adjuvant chemotherapy for non-central nervous system tumours and is primarily focused on breast cancer. CRCI is characterized as deficits in areas of cognition including memory, attention, concentration, and executive function. Development of CRCI can impair quality of life and impact treatment decisions. CRCI is highly prevalent; these problems can be detected in up to 30% of patients prior to chemotherapy, up to 75% of patients report some form of CRCI during treatment, and CRCI is still present in up to 35% of patients many years following completion of treatment. While the trajectory of CRCI is becoming better understood, the mechanisms underlying the development of CRCI are still obscure; however, host characteristics, immune dysfunction, neural toxicity, and genetics may play key roles in the development and trajectory of CRCI. Intervention research is limited, though strategies to maintain function are being studied with promising preliminary findings. This review highlights key research being conducted in these areas, both in patient populations and in animals, which will ultimately result in better understanding and effective treatments for CRCI.     

Anticonvulsant effect of neural regeneration peptide 2945 on pentylenetetrazol-induced seizures in rats

Neuron regeneration peptides (NRPs) are small synthetic peptides that stimulate neural proliferation, migration, and differentiation with no apparent toxicity and high target specificity in CNS. The aim of this study was to investigate the effect of NRP2945 on seizure activity induced by pentylenetetrazol (PTZ) in rats. Using behavioural assessment and electrocorticographical recordings, the effects of different doses of NRP2945 (5–20 µg/kg) were tested on seizure attacks induced by PTZ injection. In addition, the effect of NRP2945 was evaluated on the production of dark neurons and expression of GABA_A receptor α and β subunits and GAD-65 in the hippocampus and somatosensory cortex of the rat brain. Intraperitoneal injection of NRP2945 at 20 µg/kg prevented seizure attacks after PTZ injection. NRP2945 at doses of 5 and 10 µg/kg significantly decreased the total duration of seizure attacks and reduced the amplitude, duration and latency of epileptiform burst discharges induced by PTZ. In addition, the peptide significantly inhibited the production of dark neurons in the hippocampus and somatosensory cortex of epileptic rats. NRP2945 also significantly increased the expression of GABA_A receptor α and β subunits and GAD-65 in the hippocampus and somatosensory cortex compared with PTZ treated rats. This study indicates that NRP2945 is able to prevent the seizure attacks and neuronal injuries induced by PTZ, likely by stimulating GABA_A and GAD-65 protein expression and/or protecting these components of GABAergic signalling from PTZ-induced alteration. Further studies are needed to elucidate the potential role of NRP2945 as an antiepileptic drug.     

Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazol-induced seizures in rats

ObjectiveDocosahexaenoic acid (DHA), an omega-3 fatty acid, has been reported to raise seizure thresholds. The purpose of the present study was to test the acute anticonvulsant effects of unesterified DHA in rats, using the maximal pentylenetetrazol (PTZ) seizure model, and also to examine DHA incorporation and distribution into blood serum total lipids and brain phospholipids and unesterified fatty acids. Sedation was measured to monitor for the potential toxicity of DHA.MethodsMale Wistar rats received subcutaneous injections of saline, oleic acid (OA), or DHA. An initial pilot study (Experiment 1) established 400 mg/kg as an effective dose of DHA in the maximal PTZ seizure test. A subsequent time–response study, using 400 mg/kg (Experiment 2), established 1 hour as an effective postinjection interval for administering DHA subcutaneously. A final study (Experiment 3) comprised two different groups. The first group (“seizure-tested rats”) received saline, OA, or DHA (400 mg/kg) subcutaneously, and were seizure tested in the maximal PTZ test 1 hour later to confirm the seizure latency measurements at that time. The second group (“assay rats”) received identical subcutaneous injections of saline, OA, or DHA (400 mg/kg). One hour postinjection, however, they were sacrificed for assay rather than being seizure tested. Assays involved the analysis of serum and brain DHA. Sedation was measured in both Experiment 3 groups during the 1-hour period prior to seizure testing or sacrifice.ResultsAs noted above, 400 mg/kg proved to be an effective subcutaneous dose of DHA (Experiment 1), and 1 hour proved to be the most effective injection–test interval (Experiment 2). In Experiment 3, in the seizure-tested animals, subcutaneous administration of 400 mg/kg of DHA significantly increased latency to PTZ seizure onset 1 hour postinjection relative to the saline- and OA-injected controls, which did not differ significantly from each other (P > 0.05). In the assay animals, no significant effects of treatment on blood serum total lipids or on brain phospholipid or unesterified fatty acid profiles (P > 0.05) were observed. There were also no differences in sedation among the three groups (P > 0.05).ConclusionDHA increases resistance to PTZ-induced seizures without altering measures of sedation and, apparently, without changing DHA concentrations in serum or brain.     

Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease

BACKGROUND: The isoprostane 8,12-iso-iPF(2alpha)-VI, a specific marker of in vivo lipid peroxidation, is increased in Alzheimer disease (AD). The pathological changes associated with AD have a long silent phase before the appearance of clinical symptoms. Several studies have shown that AD is preceded by a prodromal phase characterized by mild cognitive impairment (MCI). OBJECTIVE: To investigate levels of this biomarker in subjects with MCI. DESIGN AND MAIN OUTCOME MEASURES: Using gas chromatography-mass spectrometry analysis, we measured 8,12-iso-iPF(2alpha)-VI levels in urine, plasma, and cerebrospinal fluid of patients with AD, subjects with MCI, and cognitively normal elderly subjects. SETTING AND PATIENTS: Subjects attending the Memory Disorders Clinic. RESULTS: We found significantly higher 8,12-iso-iPF(2alpha)-VI levels in cerebrospinal fluid, plasma, and urine of subjects with MCI compared with cognitively normal elderly subjects. CONCLUSIONS: These results imply that individuals with MCI have increased brain oxidative damage before the onset of symptomatic dementia. Measurement of this isoprostane may identify a subgroup of patients with MCI with increased lipid peroxidation who are at increased risk to progress to symptomatic AD.