Hippocampal Neuronal Loss Research Articles

Amentoflavone protects hippocampal neurons: anti-inflammatory, antioxidative, and antiapoptotic effects.

Amentoflavone is a natural biflavone compound with many biological properties, including anti-inflammatory, antioxidative, and neuroprotective effects. We presumed that amentoflavone exerts a neuroprotective effect in epilepsy models. Prior to model establishment, mice were intragastrically administered 25 mg/kg amentoflavone for 3 consecutive days. Amentoflavone effectively prevented pilocarpine-induced epilepsy in a mouse kindling model, suppressed nuclear factor-κB activation and expression, inhibited excessive discharge of hippocampal neurons resulting in a reduction in epileptic seizures, shortened attack time, and diminished loss and apoptosis of hippocampal neurons. Results suggested that amentoflavone protected hippocampal neurons in epilepsy mice via anti-inflammation, antioxidation, and antiapoptosis, and then effectively prevented the occurrence of seizures.

Hydrogen Sulfide Inhalation Improves Neurological Outcome via NF-κB-Mediated Inflammatory Pathway in a Rat Model of Cardiac Arrest and Resuscitation

Background/Aims: The effects of H₂S on cerebral inflammatory reaction after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) remain poorly understood. In this study, we investigated the effects of exogenous 40 ppm and 80 ppm H₂S gas on inflammatory reaction and neurological outcome after CA/CPR. Methods: CA was induced by ventricular fibrillation and followed by CPR. Forty or 80 ppm H₂S was inhaled for 1 h immediately following CPR. The levels of IL-1ß, IL-6 and TNF-a, the myeloperoxidase (MPO) activity, the expression of iNOS and ICAM-1, and the phosphorylation and translocation of NF-κB were evaluated at 24 h after CA/CPR. The tape removal test, survival rate and hippocampal neuronal counts were investigated at 14 d after CA/CPR. Results: CA/CPR induced significant increases in IL-1ß, IL-6, TNF-a and MPO activity. The phosphorylation and translocation of NF-κB, and the expression of iNOS and ICAM-1 were increased significantly. Inhalation of 40 or 80 ppm H₂S gas decreased these inflammatory cytokines. Furthermore, 40 or 80 ppm H₂S inhibited the activation of NF-κB and the downstream proinflammatory mediators iNOS and ICAM-1. H₂S inhalation also improved neurological function, 14-d survival rate, and reduced hippocampal neuronal loss. Conclusion: These results indicated that inhalation of H₂S protected against brain injury after CA/CPR. The mechanisms underlying protective effects of H₂S were associated with the inhibition of CA/CPR-induced inflammation reactions by reducing IL-1ß, IL-6 and TNF-a, and concomitantly inhibiting the activation and infiltration of neutrophils. The beneficial effects of H₂S might be mediated by downregulation of NF-κB and the downstream proinflammatory signaling pathway.

Curcumin-Protected PC12 Cells Against Glutamate-Induced Oxidative Toxicity.

Glutamate is a major excitatory neurotransmitter present in the central nervous system. The glutamate/cystine antiporter system x c- connects the antioxidant defense with neurotransmission and behaviour. Overactivation of ionotropic glutamate receptors induces neuronal death, a pathway called excitotoxicity. Glutamate-induced oxidative stress is a major contributor to neurodegenerative diseases including cerebral ischemia, Alzheimer's and Huntington's disease. Curcuma has a wide spectrum of biological activities regarding neuroprotection and neurocognition. By reducing the oxidative damage, curcumin attenuates a spinal cord ischemia-reperfusion injury, seizures and hippocampal neuronal loss. The rat pheochromocytoma (PC12) cell line exhibits many characteristics useful for the study of the neuroprotection and neurocognition. This investigation was carried out to determine whether the neuroprotective effects of curcumin can be observed via the glutamate-PC12 cell model. Results indicate that glutamate (20 mM) upregulated glutathione peroxidase 1, glutathione disulphide, Ca2+ influx, nitric oxide production, cytochrome c release, Bax/Bcl-2 ratio, caspase-3 activity, lactate dehydrogenase release, reactive oxygen species, H 2 O 2 , and malondialdehyde; and downregulated glutathione, glutathione reductase, superoxide dismutase and catalase, resulting in enhanced cell apoptosis. Curcumin alleviates all these adverse effects. Conclusively, curcumin can effectively protect PC12 cells against the glutamate-induced oxidative toxicity. Its mode of action involves two pathways: the glutathione-dependent nitric oxide-reactive oxygen species pathway and the mitochondria-dependent nitric oxide-reactive oxygen species pathway.

Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus.

BackgroundNLRP3 inflammasome is proposed to regulate inflammation in several neurological diseases, but its role in epilepsy remains largely unknown. This study aimed to investigate the role of the NLRP3 inflammasome in neuroinflammation, spontaneous recurrent seizures (SRS) and hippocampal neuronal loss in rat brain following amygdala kindling-induced status epilepticus (SE).MethodsWe detected the protein levels of IL-1β and NLRP3 inflammasome components by Western blot in the hippocampus of shams and SE rats at different time points following SE. To further examine whether the activation of the NLRP3 inflammasome contributes to SE-associated neuronal damage, we employed a nonviral strategy to knock down NLRP3 and caspase-1 expression in brain before undergoing SE. Proinflammatory cytokine levels and hippocampal neuronal loss were evaluated at 12 hours and at 6 weeks following SE respectively in these NLRP3 and caspase-1 deficient rats. Meanwhile, SRS occurrence was evaluated through a 4-week video recording started 2 weeks after SE in these NLRP3 and caspase-1 deficient rats.ResultsIL-1β levels and NLRP3 inflammasome components levels dramatically increased at 3 hours after SE, and reached a maximum at 12 hours after SE compared with the control group. Knock down of NLRP3 or caspase-1 decreased the levels of IL-1β and IL-18 at 12 hours after SE, which was accompanied by a significant suppression in the development and severity of SRS during the chronic epileptic phase. Meanwhile, knock down of NLRP3 or caspase-1 led to a remarkable reduction of hippocampal neuronal loss in the CA1 and CA3 area of the hippocampus at 6 weeks after SE.ConclusionsOur study provides the first evidence that the NLRP3 inflammasome was significantly up-regulated following SE. More importantly, we show that inhibition of the NLRP3 inflammasome provides neuroprotection in rats following SE. These findings suggest that NLRP3 may represent a potential target for the treatment of epileptogenesisElectronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0212-5) contains supplementary material, which is available to authorized users.

A putative role for homocysteine in the pathophysiology of acute bacterial meningitis in children.

BackgroundAcute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae. Neuron death in acute bacterial meningitis involves the excessive activation of NMDA receptors and p53-mediated apoptosis, and the latter is triggered by the depletion of NAD + and ATP cellular stores by the DNA repair enzyme poly(ADP-ribose) polymerase. This enzyme is activated during acute bacterial meningitis in response to DNA damage induced, on its turn, by reactive oxygen and nitrogen species. An excess of homocysteine can also induce this cascade of events in hippocampal neurons.The present work aimed at investigating the possible involvement of homocysteine in the pathophysiology of meningitis by comparing its concentrations in cerebrospinal fluid (CSF) samples from children with viral or acute bacterial meningitis, and control individuals.MethodsHomocysteine and cysteine concentrations were assessed by high-performance liquid chromatography in CSF samples from nine patients with acute bacterial meningitis, 13 patients with viral meningitis and 18 controls (median age: 4 years-old; range: <1 to 13) collected by lumbar puncture at admission at the Children's Hospital Joao Paulo II - FHEMIG, from January 2010 to November 2011.ResultsWe found that homocysteine accumulates up to neurotoxic levels within the central nervous system of patients with acute bacterial meningitis, but not in those with viral meningitis or control individuals. No correlation was found between homocysteine and cysteine concentrations and the cerebrospinal fluid standard cytochemical parameters.ConclusionsOur results suggest that HCY is produced intrathecally in response to acute bacterial meningitis and accumulates within the central nervous system reaching potentially neurotoxic levels. This is the first work to propose a role for HCY in the pathophysiology of brain damage associated with acute bacterial meningitis.

Aberrant expression of miR-218 and miR-204 in human mesial temporal lobe epilepsy and hippocampal sclerosis-convergence on axonal guidance.

Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS. miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay. miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204. miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS.

Persistent reduction of hippocampal glutamine synthetase expression after status epilepticus in immature rats.

Mesiotemporal sclerosis (MTS), the most frequent form of drug-resistant temporal lobe epilepsy, often develops after an initial precipitating injury affecting the immature brain. To analyse early processes in epileptogenesis we used the juvenile pilocarpine model to study status epilepticus (SE)-induced changes in expression of key components in the glutamate-glutamine cycle, known to be affected in MTS patients. SE was induced by Li(+) /pilocarpine injection in 21-day-old rats. At 2-19 weeks after SE hippocampal protein expression was analysed by immunohistochemistry and neuron damage by FluoroJade staining. Spontaneous seizures occurred in at least 44% of animals 15-18 weeks after SE. As expected in this model, we did not observe loss of principal hippocampal neurons. Neuron damage was most pronounced in the hilus, where we also detected progressive loss of parvalbumin-positive GABAergic interneurons. Hilar neuron loss (or end-folium sclerosis), a common feature in patients with MTS, was accompanied by a progressively decreased glutamine synthetase (GS)-immunoreactivity from 2 (-15%) to 19 weeks (-33.5%) after SE. Immunoreactivity for excitatory amino-acid transporters, vesicular glutamate transporter 1 and glial fibrillary acidic protein was unaffected. Our data show that SE elicited in 21-day-old rats induces a progressive reduction in hilar GS expression without affecting other key components of the glutamate-glutamine cycle. Reduced expression of glial enzyme GS was first detected 2 weeks after SE, and thus clearly before spontaneous recurrent seizures occurred. These results support the hypothesis that reduced GS expression is an early event in the development of hippocampal sclerosis in MTS patients and emphasize the importance of astrocytes in early epileptogenesis.

O-215 Necrotizing Enterocolitis Is Associated With Hippocampal Neuron Loss, Microglial Activation And Increased Il-8 Levels In Preterm Pigs

Background and aims Preterm birth predisposes to neurological sequelae. Necrotizing enterocolitis (NEC) may further increase the susceptibility to neurological damage, possibly via gut-derived inflammatory signals. To investigate this, we test if NEC severity and intestinal permeability in formula-fed preterm pigs is associated with histopathology, microglial activation, and increased proinflammatory cytokine levels in the hippocampus. Methods Forty-four preterm piglets were fed increasing doses of formula and euthanized on day five. Macroscopic NEC lesions were scored in five regions of the gut (stomach, proximal, middle, and distal small intestine, colon). Intestinal permeability was assessed by urinary lactulose-mannitol-ratio. Hippocampal IL-1β and IL-8 levels were determined by ELISA. Histopathology, neurodegeneration, and microglia were investigated by analyses of hematoxylin-eosin, Fluoro-jade B (FJB), and Iba-1 stained coronal sections, respectively. Results Proximal, middle, and distal small intestinal NEC score, and intestinal permeability correlated positively with IL-8 levels (all p Conclusions Acute development of NEC is associated with neuron loss, microglial activation, and increased IL-8 levels in the hippocampus of preterm pigs. Gut inflammatory disorders and increased intestinal permeability may affect the immature brain and contribute to long term neurological disorders.

Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

Haploinsufficiency of progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD), and modulates an innate immune response in humans and mouse models. GRN polymorphism may be linked to late-onset Alzheimer’s disease (AD). However, PRGN’s role in AD pathogenesis is unknown. Here, we show PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial PGRN in AD mice impaired phagocytosis and increased plaque load threefold. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing PGRN’s dose-dependent inhibitory effects on plaque deposition. PGRN also protected against Aβ toxicity. Reducing microglial PGRN exacerbated cognitive deficits in AD mice. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. PGRN’s protective effects against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTD and AD.

Hypoxia inducible factor-1α expression is associated with hippocampal apoptosis during epileptogenesis

Cell apoptosis can cause hippocampal neuronal loss after epileptic seizures. Hypoxia inducible factor (HIF)-1α is an important factor mediating apoptosis after brain injuries, such as cerebral ischemia and traumatic brain injures, but little research has been done on its role in the lithium chloride–pilocarpine induced epileptic model. Here, we used a rat model of pilocarpine-induced status epilepticus (SE) to investigate HIF-1α expression and apoptosis in the hippocampus, and to explore their relationship during epileptogenesis. 120 male Sprague Dawley (SD) rats were treated with lithium chloride–pilocarpine injections and divided into an experimental group (administered by MK-801) and a positive control group (administered by saline). Then the HIF-1α expression and hippocampal apoptosis were investigated by histological confirmation and western blotting at 24h, 3d, 7d and 14d, respectively. The results showed that the administration of MK-801 significantly reduced (P<0.05) HIF-1α expression and hippocampal apoptosis during epileptogenesis in comparison with the positive control. Moreover, the expression of HIF-1α and hippocampal apoptosis presented significant time-dependent changes (P<0.01) within 2 weeks, and their positive correlation (P<0.05) analyzed by Pearson׳s correlation analysis. Meanwhile, the HIF-1α immunostained cells were distributed in accord with TUNEL immunostained cells and Caspase-3 immunopositive cells in the hippocampus. These results indicate that the HIF-1α expression is associated with hippocampal apoptosis, and suggest that HIF-1α is an important factor during epileptogenesis.

Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection.

Pediatric HIV infection remains a global health crisis with a worldwide infection rate of 2.5 million (WHO, Geneva Switzerland, 2009). Children are much more susceptible to HIV-1 neurological impairments compared with adults, which is exacerbated by coinfections. A major obstacle in pediatric HIV research is sample access. The proposed studies take advantage of ongoing pediatric simian immunodeficiency virus (SIV) pathogenesis and vaccine studies to test the hypothesis that pediatric SIV infection diminishes neuronal populations and neurogenesis in the hippocampus. Newborn rhesus macaques (Macaca mulatta) that received intravenous inoculation of highly virulent SIVmac251 (n=3) or vehicle (control n=4) were used in this study. After a 6-18-week survival time, the animals were euthanized and the brains prepared for quantitative histopathological analysis. Systematic sections through the hippocampus were either Nissl stained or immunostained for doublecortin (DCX+), a putative marker of immature neurons. Using design-based stereology, we report a 42% reduction in the pyramidal neuron population of the CA1, CA2, and CA3 fields of the hippocampus (P<0.05) in SIV-infected infants. The DCX+ neuronal population was also significantly reduced within the dentate gyrus of the hippocampus. The loss of hippocampal neurons and neurogenic capacity may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. These data suggest that pediatric SIV infection, which leads to significant neuronal loss in the hippocampus within 3 months, closely models a subset of pediatric HIV infections with rapid progression.

Hippocampal adaptive response following extensive neuronal loss in an inducible transgenic mouse model.

Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DTA mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.

Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice

Global cerebral ischemia/reperfusion (GCI/R) injury encompasses complex pathophysiological sequalae, inducing loss of hippocampal neurons and behavioural deficits. Progressive neuronal death and memory dysfunctions culminate from several different mechanisms like oxidative stress, excitotoxicity, neuroinflammation and cholinergic hypofunction. Experimental evidences point to the beneficial effects of cholinomimetic agents such as rivastigmine and galantamine in improving memory outcomes following GCI/R injury. However, the direct implications of muscarinic and nicotinic receptor blockade during global cerebral ischemia/reperfusion injury have not been investigated. Therefore, we evaluated the relative involvement of muscarinic and nicotinic receptors in spatial/associative memory functions and neuronal damage during global cerebral ischemia reperfusion injury. The outcomes of present study support the idea that preservation of both muscarinic and nicotinic receptor functions is essential to alleviate hippocampal neuronal death in CA1 region following global cerebral ischemia/reperfusion injury.

Folliculo-stellate cells – Potential mediators of the inflammaging-induced hyperactivity of the hypothalamic–pituitary–adrenal axis in healthy elderly individuals

Some evidence has suggested that, with age, the hypothalamic–pituitary–adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood–brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.

Hippocampal damage and affective disorders after treatment of cerebral aneurysms.

Despite good neurological outcome after the treatment of ruptured or incidental cerebral aneurysms, many patients complain about mood disturbances such as anxiety and depression. The present study investigated the nature of these affective disorders, their trigger factors, and corresponding structural brain changes. We assessed 63 patients matched by history of previous subarachnoid hemorrhage (SAH) and treatment modality (clipping vs. coiling) by a test battery including the Hospital Anxiety and Depression Scale (HADS) and beck depression inventory-II (BDI-II). MR imaging for the evaluation of structural changes included H(1)-MR spectroscopy, hippocampal volumetry, and diffusion tensor imaging (DTI). The applied multimodal imaging revealed no significant differences between patients with previous SAH and patients with incidental aneurysms; there were also no substantial differences between patients with and without previous SAH with respect to depression and anxiety. However, we observed significantly higher mean HADS scores in patients treated surgically versus patients treated by coiling (p < 0.01). BDI-II tended to be higher in surgically treated patients, but this difference appeared statistically insignificant. Surgically treated patients displayed substantial hippocampal damage in all imaging techniques: reduction in mean concentrations of N-acetylaspartate (p = 0.04), hippocampal volume reduction (p = 0.012), and diffusion disorder (p = 0.02). The structural alterations correlated significantly with the increased HADS scores. In contrast to endovascular treatment, aneurysm surgery seems to be associated with an increased incidence of mood disorders corresponding to hippocampal neuronal loss, independent of preceding SAH.

Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity.

ObjectivesDiabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts.MethodsHippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined.ResultsThe levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus.InterpretationThese data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.

Disease-modifying effects of RHC80267 and JZL184 in a pilocarpine mouse model of temporal lobe epilepsy.

Patients with temporal lobe epilepsy (TLE) often suffer from comorbid psychiatric diagnoses such as depression, anxiety, or impaired cognitive performance. Endocannabinoid (eCB) signaling is a key regulator of synaptic neurotransmission and has been implicated in the mechanisms of epilepsy as well as several mood disorders and cognitive impairments. We employed a pilocarpine model of TLE in C57/BJ mice to investigate the role of eCB signaling in epileptogenesis and concomitant psychiatric comorbidities. We sought to alter the neuronal levels of a known eCB receptor ligand, 2-arachidonylglycerol (2-AG), through the use of RHC80267 or JZL184. Pilocarpine-treated mice were treated with RHC80267 (1.3 μmol) or JZL184 (20 mg/kg) immediately after the termination of status epilepticus (SE), which was followed by daily treatment for the next 7 days. Our results indicated that RHC80267 treatment significantly reduced the percentage of mice suffering from spontaneous recurrent seizures (SRS) in addition to decreasing the duration of observed seizures when compared to vehicle treatment. Furthermore, RHC80267 attenuated depression and anxiety-related behaviors, improved previously impaired spatial learning and memory, and inhibited seizure-induced hippocampal neuronal loss during the chronic epileptic period. In contrast, JZL184 administration markedly increased the frequency and the duration of observed SRS, enhanced the previously impaired neuropsychological performance, and increased hippocampal damage following SE. These findings suggest that RHC80267 treatment after the onset of SE could result in an amelioration of the effects found during the chronic epileptic period and yield an overall decrease in epileptic symptoms and comorbid conditions. Thus, alterations to endocannabinoid signaling may serve as a potential mechanism to prevent epileptogenesis and manipulation of this signaling pathway as a possible drug target.

Research of fenvalerate induce hippocampal neurons injury through interfering with estrogen action

To investigate whether fenvalerate can induce mouse hippocampal nerve cell damage by interfering with estrogen (E2) effect. Hippocampus were dissected and cultured from Embryo 18 d ICR mice, the cells were cultured for 7 days. Fenvalerate (FEN, 0, 1, 10, 50 µg/ml), FEN (10, 50 µg/ml) and estrogen receptor antagonist ICI 182, 780 (1 µmol/L), FEN (0, 10, 50 µg/ml) and E2 (10 nmol/L) were applied to the cultured cells for 48h. Immunocytochemically stained with neurons and astrocytes to evaluate the levels respectively, and the growth of neurite. Result 1µg/ml FEN have no effect on neurons, neurites and protoplasmic astrocytes, 10 and 50 µg/ml FEN can significantly decrease the neuron viability and the length of neurite as well as increase the level of protoplasmic astrocytes (P < 0.05 vs. control group). ICI 182, 780 alone have no effect on neurons, neurites and protoplasmic astrocytes; ICI+10 µg/ml FEN significantly increase the cell viability and extend neurite length as well as decrease protoplasmic astrocytes (P < 0.05 vs. 10 µg/ml FEN alone group); ICI+50 µg/ml FEN significantly increase the cell viability and decrease protoplasmic astrocytes (P < 0.05 vs. 50 µg/ml FEN alone group). E2 alone have no effect on protoplasmic astrocytes, while can promote neuronal survival and neurite growth; E2+10 µg/ml FEN and E2+50 µg/ml FEN significantly decrease neuronal survival and neurite growth, as well as increase protoplasmic astrocytes (P < 0.05 vs. E2 alone group). Fenvalerate can induce the loss of hippocampal neurons through disrupting estrogen nuclear receptor signaling, and inhibit the length of neurite through disrupting estrogen nuclear receptor and membrane receptor signaling. The effect of estrogen disruption play an important role in developmental neurotoxicity by fenvalerate.

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury

Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model.

Hippocampal sclerosis in feline epilepsy.

Hippocampal sclerosis (HS) refers to loss of hippocampal neurons and astrogliosis. In temporal lobe epilepsy (TLE), HS is a key factor for pharmacoresistance, even though the mechanisms are not quite understood. While experimental TLE models are available, there is lack of models reflecting the natural HS development. Among domestic animals, cats may present with TLE-like seizures in natural and experimental settings. With this study on the prevalence, segmental pattern and clinicopathological correlates of feline HS, we evaluated the translational value for human research. Evaluation schemes for human brains were applied to epileptic cats. The loss of neurons was morphometrically assessed and the degree of gliosis was recorded. Hippocampal changes resembling human HS were seen in about one third of epileptic cats. Most of these were associated with infiltrative diseases such as limbic encephalitis. Irrespective of the etiology and semiology of seizures, total hippocampal sclerosis was the most prevalent form seen in epileptic animals. Other HS types also occur at varying frequencies. Segmental differences to human HS can be explained by species-specific synaptic connectivities and a different spectrum of etiologies. All these variables require consideration when translating results from feline studies regarding seizure-associated changes of the temporal lobe and especially HS.