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Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion.

ABSTRACT: Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-? (A?) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of A? and vascular inflammatory markers. GSNO treatment (50 ?g/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the A? levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NF?B and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial A? uptake. Additionally, GSNO treatment inhibited the ?-secretase activity in primary rat neuron cell culture, thus reducing secretion of A?, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease.

SUBMITTER: Won JS

PROVIDER: S-EPMC4040220 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion.

Won Je-Seong JS Kim Jinsu J Annamalai Balasubramaniam B Shunmugavel Anandakumar A Singh Inderjit I Singh Avtar K AK

Journal of Alzheimer's disease : JAD 20130101 3

Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effe ...[more]

PMID: 23254638

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Project description:ObjectiveCurrently, most models of vascular cognitive impairment are established by occluding the carotid arteries uni- or bilaterally to reduce the cerebral blood flow mimicking chronic cerebral hypoxia. Due to the sudden blood flow interruption, a gradual narrowing of the carotid artery cannot be completely imitated. This paper aims to establish a bilateral carotid stenosis model with mild cognitive dysfunction and mild white matter changes to simulate patients with vascular predementia.MethodsAged Wistar rats (18 months old) underwent either bilateral common carotid artery stenosis (BCAS) or occlusion (BCAO) surgery or a sham operation (control group). The cerebral blood flow in the frontal cortex was measured using Doppler flowmetry. Thirty days after surgery, cognitive function impairments were determined with the Morris water maze; cerebral magnetic resonance imaging was performed to detect changes in fractional anisotropy to assess white matter injuries, and histological studies were performed.ResultsThe aged rats in the BCAS group showed a more gradual cerebral blood flow reduction and a lower mortality rate (11%) compared to rats in the BCAO group. The water maze test revealed a more marginal impairment affecting spatial learning and memory in rats with BCAS than in rats with BCAO. Diffusion tensor imaging detected white matter injuries in the hippocampus and cerebral cortex of BCAS rats. Particularly, a small portion of nerve fibers of the lateral somatosensory cortex was significantly different between rats of the BCAO and BCAS groups. In the BCAS group, the microscopic structure of the hippocampal CA1 region changed slightly after 30 days and sustained a slight mitochondrial crista crack. Fluorescence staining indicated that the number of GFAP-positive cells was increased in rat brains of the BCAS group, and this phenomenon was even more pronounced in the BCAO group. The hnRNPA2/B1 and GABAAR-α1 expression levels were significantly decreased in the hippocampus of rats with BCAS compared to those of controls.ConclusionSevere bilateral carotid stenosis induced mild cognitive dysfunction and slight structural changes in the brains of aged rats. Thus, a chronic cerebral hypoperfusion model was successfully established.

Project description:AimsClear roles and mechanisms in explaining gut microbial dysbiosis and microbial metabolites short-chain fatty acids (SCFAs) alterations in chronic cerebral ischemic pathogenesis have yet to be explored. In this study, we investigated chronic cerebral hypoperfusion (CCH)-induced gut microbiota and metabolic profiles of SCFAs as well as the effects and mechanisms of fecal microbiota transplantation (FMT) and SCFAs treatment on CCH-induced hippocampal neuronal injury.MethodsBilateral common carotid artery occlusion (BCCAo) was used to establish the CCH model. Gut microbiota and SCFAs profiles in feces and hippocampus were evaluated by 16S ribosomal RNA sequencing and gas chromatography-mass spectrometry. RNA sequencing analysis was performed in hippocampal tissues. The potential molecular pathways and differential genes were verified through western blot, immunoprecipitation, immunofluorescence, and ELISA. Cognitive function was assessed via the Morris water maze test. Ultrastructures of mitochondria and synapses were tested through a transmission electron microscope.ResultsChronic cerebral hypoperfusion induced decreased fecal acetic and propionic acid and reduced hippocampal acetic acid, which were reversed after FMT and SCFAs administration by changing fecal microbial community structure and compositions. Furthermore, in the hippocampus, FMT and SCFAs replenishment exerted anti-neuroinflammatory effects through inhibiting microglial and astrocytic activation as well as switching microglial phenotype from M1 toward M2. Moreover, FMT and SCFAs treatment alleviated neuronal loss and microglia-mediated synaptic loss and maintained the normal process of synaptic vesicle fusion and release, resulting in the improvement of synaptic plasticity. In addition, FMT and SCFAs supplement prevented oxidative phosphorylation dysfunction via mitochondrial metabolic reprogramming. The above effects of FMT and SCFAs treatment led to the inhibition of CCH-induced cognitive impairment.ConclusionOur findings highlight FMT and SCFAs replenishment would be the feasible gut microbiota-based strategy to mitigate chronic cerebral ischemia-induced neuronal injury.

Project description:Chronic cerebral hypoperfusion during aging may cause progressive neurodegeneration as ischemic conditions persist. Proper functioning of the interplay between neurons and glia is fundamental for the functional organization of the brain. The aim of our research was to study the pathophysiological mechanisms, and particularly the derangement of the interplay between neurons and astrocytes-microglia with the formation of "triads," in a model of chronic cerebral hypoperfusion induced by the two-vessel occlusion (2VO) in adult Wistar rats (n = 15). The protective effect of dipyridamole given during the early phases after 2VO (4 mg/kg/day i.v., the first 7 days after 2VO) was verified (n = 15). Sham-operated rats (n = 15) were used as controls. Immunofluorescent triple staining of neurons (NeuN), astrocytes (GFAP), and microglia (IBA1) was performed 90 days after 2VO. We found significantly higher amount of "ectopic" neurons, neuronal debris and apoptotic neurons in CA1 Str. Radiatum and Str. Pyramidale of 2VO rats. In CA1 Str. Radiatum of 2VO rats the amount of astrocytes (cells/mm(2)) did not increase. In some instances several astrocytes surrounded ectopic neurons and formed a "micro scar" around them. Astrocyte branches could infiltrate the cell body of ectopic neurons, and, together with activated microglia cells formed the "triads." In the triad, significantly more numerous in CA1 Str. Radiatum of 2VO than in sham rats, astrocytes and microglia cooperated in the phagocytosis of ectopic neurons. These events might be common mechanisms underlying many neurodegenerative processes. The frequency to which they appear might depend upon, or might be the cause of, the burden and severity of neurodegeneration. Dypiridamole significantly reverted all the above described events. The protective effect of chronic administration of dipyridamole might be a consequence of its vasodilatory, antioxidant and anti-inflammatory role during the early phases after 2VO.

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Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion.

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Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion.

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