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Conditional expression of human β-hexosaminidase in the neurons of Sandhoff disease rescues mice from neurodegeneration but not neuroinflammation  [cached]
Kyrkanides Stephanos,Brouxhon Sabine M,Tallents Ross H,Miller Jen-nie H
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-186
Abstract: This study evaluated whether GM2 ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB / mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB / mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB / mice from GM2 neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM2 presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored.
Delayed Post - Traumatic Haemorrhage of the Brain
N. O. Ameli,Ch. M. ( B' ham ),F. R. C. S. ( E ). F. I. C. S.
Acta Medica Iranica , 1957,
Abstract: 15 cases of delayed post-traumatic haemorrhage of the brain are described. The lucid interval varied from 2 hours to one month. In at least seven cases a predisposing factor had been present. The importance of small angioma as a factor in young people has been emphasized. Clinical and pathological aspects and treatment discussed.
Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus
Cristina Pintado, María P Gavilán, Elena Gavilán, Luisa García-Cuervo, Antonia Gutiérrez, Javier Vitorica, Angélica Casta?o, Rosa M Ríos, Diego Ruano
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-87
Abstract: Young male Wistar rats were injected with 1 μL of saline or LPS (5?mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 μL of LPS and 24 h later 1 μL (5?mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining.LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone.Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases.
Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration
Liya Qin, Fulton T Crews
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-130
Abstract: Polyinosine-polycytidylic acid (poly I:C) was used to induce inflammatory responses when sensitized with D-galactosamine (D-GalN). Male C57BL/6 mice were treated with water or ethanol (5?g/kg/day, i.g., 10?days) or poly I:C (250?μg/kg, i.p.) alone or sequentially 24 hours after ethanol exposure. Cytokines, chemokines, microglial morphology, NADPH oxidase (NOX), reactive oxygen species (ROS), high-mobility group box 1 (HMGB1), TLR3 and cell death markers were examined using real-time PCR, ELISA, immunohistochemistry and hydroethidine histochemistry.Poly I:C increased blood and brain TNFα that peaked at three hours. Blood levels returned within one day, whereas brain levels remained elevated for at least three days. Escalating blood and brain proinflammatory responses were found with ethanol, poly I:C, and ethanol-poly I:C treatment. Ethanol pretreatment potentiated poly I:C-induced brain TNFα (345%), IL-1β (331%), IL-6 (255%), and MCP-1(190%). Increased levels of brain cytokines coincided with increased microglial activation, NOX gp91phox, superoxide and markers of neurodegeneration (activated caspase-3 and Fluoro-Jade B). Ethanol potentiation of poly I:C was associated with ethanol-increased expression of TLR3 and endogenous agonist HMGB1 in the brain. Minocycline and naltrexone blocked microglial activation and neurodegeneration.Chronic ethanol potentiates poly I:C blood and brain proinflammatory responses. Poly I:C neuroinflammation persists after systemic responses subside. Increases in blood TNFα, IL-1β, IL-6, and MCP-1 parallel brain responses consistent with blood cytokines contributing to the magnitude of neuroinflammation. Ethanol potentiation of TLR3 agonist responses is consistent with priming microglia-monocytes and increased NOX, ROS, HMGB1-TLR3 and markers of neurodegeneration. These studies indicate that TLR3 agonists increase blood cytokines that contribute to neurodegeneration and that ethanol binge drinking potentiates these responses.
Neuroinflammation and Neurodegeneration in Adult Rat Brain from Binge Ethanol Exposure: Abrogation by Docosahexaenoic Acid  [PDF]
Nuzhath Tajuddin, Kwan-Hoon Moon, S. Alex Marshall, Kimberly Nixon, Edward J. Neafsey, Hee-Yong Kim, Michael A. Collins
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101223
Abstract: Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ~9 g/kg/d, achieving blood ethanol levels ~375 mg/dl; “Majchrowicz” model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model—hippocampus, entorhinal cortex, and olfactory bulb—but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain “oxidative stress footprints” (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (~60 d) were ethanol-binged (100 mM or ~450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain.
Influence of Post-Traumatic Stress Disorder on Neuroinflammation and Cell Proliferation in a Rat Model of Traumatic Brain Injury  [PDF]
Sandra A. Acosta, David M. Diamond, Steven Wolfe, Naoki Tajiri, Kazutaka Shinozuka, Hiroto Ishikawa, Diana G. Hernandez, Paul R. Sanberg, Yuji Kaneko, Cesar V. Borlongan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081585
Abstract: Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients.
Delayed traumatic spinal epidural hematoma with neurological deficits  [PDF]
Luciano Miller Reis Rodrigues,Felipe Abreu,Edison Noboru Fujiki,Carlo Milani
Einstein (S?o Paulo) , 2010,
Abstract: To describe the mechanism that causes spinal epidural hematoma with neurologic deficit and review the literature. We report a case of a 62-year-old man with post-traumatic epidural hematoma in the cervicothoracic spine, who developed progressive neurological deficit which eventually resulted in complete paralysis below T1. During surgical evacuation significant spine compression due to an organizing hematoma was observed. After surgery, the patient’s motor function improved and there was a complete recovery of the neurologic deficit after a rehabilitation program. Conclusion: Epidural hematoma can happen after delayed traumatic event leading to a variable degree of neurologic damage.
Mild traumatic brain injury: a risk factor for neurodegeneration
Brandon E Gavett, Robert A Stern, Robert C Cantu, Christopher J Nowinski, Ann C McKee
Alzheimer's Research & Therapy , 2010, DOI: 10.1186/alzrt42
Abstract: A complex interaction between genetic and environmental risk factors has often been a suspected trigger for the development of neurodegenerative disease. Yet of all the possible environmental risk factors put forth, trauma to the central nervous system is one of the most consistent candidates for initiating the molecular cascades that result in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis [1-3]. Recent evidence also suggests that mild traumatic brain injury (TBI), including repetitive concussive and subconcussive trauma, can provoke another distinctive neurodegeneration: chronic traumatic encephalopathy (CTE) [4].CTE has to date only been described neuropathologically in individuals with a history of repetitive closed head injury, most often occurring in the context of contact sports. It remains to be determined whether there is a genetic susceptibility to the development of CTE and whether a single severe traumatic head injury may also be causative.CTE is a progressive tauopathy with a distinct clinical and neuropathological profile that becomes symptomatic many years after an individual experiences repeated concussive or subconcussive blows to the head. The characteristic features of CTE include: extensive tau immunoreactive neurofibrillary tangles and astrocytic tangles throughout the frontal and temporal cortices in a patchy, superficial distribution, with focal epicenters at the depths of sulci and around small vessels; extensive tau neurofibrillary tangles in the limbic and paralimbic regions, diencephalon, basal ganglia and brainstem; and a relative paucity of β-amyloid (Aβ) deposits, although diffuse plaques are present in roughly one-half of the cases. In advanced disease, there are also macroscopic abnormalities: generalized cerebral atrophy and enlarged ventricles; atrophy of the medial temporal lobe structures and mammillary bodies; cavum septi pellucidi, often with fenestrations; and pallor of the substantia nigr
Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease
Zuzana Stozicka, Norbert Zilka, Petr Novak, Branislav Kovacech, Ondrej Bugos, Michal Novak
Journal of Neuroinflammation , 2010, DOI: 10.1186/1742-2094-7-64
Abstract: Brains of WKY and SHR transgenic rats in the terminal stage of phenotype and their age-matched non-transgenic littermates were examined by means of immunohistochemistry and unbiased stereology. Basic measures of tau-induced neurodegeneration (load of neurofibrillary tangles) and neuroinflammation (number of Iba1-positive microglia, their activated morphology, and numbers of microglia immunoreactive for MHCII and astrocytes immunoreactive for GFAP) were quantified with an optical fractionator in brain areas affected by neurofibrillary pathology (pons, medulla oblongata). The stereological data were evaluated using two-way ANOVA and Student's t-test.Tau neurodegeneration (neurofibrillary tangles (NFTs), axonopathy) and neuroinflammation (microgliosis, astrocytosis) appeared in both WKY and SHR transgenic rats. Although identical levels of transgene expression in both lines were present, terminally-staged WKY transgenic rats displayed significantly lower final NFT loads than their SHR transgenic counterparts. Interestingly, microglial responses showed a striking difference between transgenic lines. Only 1.6% of microglia in SHR transgenic rats expressed MHCII in spite of having a robust phagocytic phenotype, whereas in WKY transgenic rats, 23.2% of microglia expressed MHCII despite displaying a considerably lower extent of transformation into phagocytic phenotype.These results show that the immune response represents a pivotal and genetically variable modifying factor that is able to influence vulnerability to neurodegeneration. Therefore, targeted immunomodulation could represent a prospective therapeutic approach to Alzheimer's disease.Alzheimer's disease (AD) is characterized by progressive neurodegeneration of the central nervous system. While the precise aetiology of this disease still remains unknown, it is believed that the intracellular accumulation of hyperphosphorylated tau, which forms neurofibrillary tangles, and the deposition of extracellular filaments, c
Post-traumatic hypoxia exacerbates neurological deficit, neuroinflammation and cerebral metabolism in rats with diffuse traumatic brain injury
Edwin B Yan, Sarah C Hellewell, Bo-Michael Bellander, Doreen A Agyapomaa, M Cristina Morganti-Kossmann
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-147
Abstract: Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O2/88% N2) or normoxic (22% O2/78% N2) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique.TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels.Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.Traumatic brain injury (TBI) remains a major health burden in both developed and developing countries. TBI consists of two temporal pathological phases spanning the initial traumatic impact and a multitude of secondary cascades, resulting in progressive tissue degeneration and neurological impairment [1-3]. The pathological consequences of TBI can be variable and largely depend on the presentation of injury as either focal or diffuse, or a combination of both. Diffuse brain injury may result from rotational forces and/or acceleration/deceleration of the head
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