Dataset Information

Rho kinase inhibitor fasudil protects against ?-amyloid-induced hippocampal neurodegeneration in rats.

ABSTRACT:

Background and purpose

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and A?-induced neuronal damage is the major pathology of AD. There is increasing evidence that neuroinflammation induced by A? is also involved in the pathogenesis of AD. Fasudil is a Rho kinase inhibitor and has been reported to have neuroprotective effects. In this study, the main purpose is to investigate whether fasudil has beneficial effects on cognitive impairment and neuronal toxicity induced by A?.

Methods and results

In the present study, intracerebroventricular injection of A?1-42 to rats resulted in marked cognitive impairment, severe neuronal damage, as well as increased IL-1?, tumor necrosis factor alpha (TNF-?) production, and NF-?B activation. Administration of fasudil significantly ameliorated the spatial learning and memory impairment, attenuated neuronal loss, and neuronal injury induced by A?1-42 . In addition, fasudil inhibited IL-1? and TNF-? production and NF-?B activation in the rat brain.

Conclusions

Fasudil can protect against A?-induced hippocampal neurodegeneration by suppressing inflammatory response, suggesting that fasudil might be a promising agent for the prevention and treatment of inflammation-related diseases, such as AD.

SUBMITTER: Song Y

PROVIDER: S-EPMC6493451 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

Rho kinase inhibitor fasudil protects against β-amyloid-induced hippocampal neurodegeneration in rats.

Song Yun Y Chen Xu X Wang Li-Yan LY Gao Wei W Zhu Mei-Jia MJ

CNS neuroscience & therapeutics 20130503 8

<h4>Background and purpose</h4>Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and Aβ-induced neuronal damage is the major pathology of AD. There is increasing evidence that neuroinflammation induced by Aβ is also involved in the pathogenesis of AD. Fasudil is a Rho kinase inhibitor and has been reported to have neuroprotective effects. In this study, the main purpose is to investigate whether fasudil has beneficial effects on cognitive impairment and neuronal toxicity indu ...[more]

PMID: 23638992

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Project description:Background and purposeGlutamate transporters play a major role in maintaining brain homeostasis and the astrocytic transporters, EAAT1 and EAAT2, are functionally dominant. Astrocytic excitatory amino acid transporters (EAATs) play important roles in various neuropathologies wherein astrocytes undergo cytoskeletal changes. Astrocytic plasticity is well documented, but the interface between EAAT function, actin and the astrocytic cytoskeleton is poorly understood. Because Rho kinase (ROCK) is a key determinant of actin polymerization, we investigated the effects of ROCK inhibitors on EAAT activity and astrocytic morphology.Experimental approachThe functional activity of glutamate transport was determined in murine cultured astrocytes after exposure to the ROCK inhibitors Fasudil (HA-1077) and Y27632 using biochemical, molecular and morphological approaches. Cytochemical analyses assessed changes in astrocytic morphology, F-/G-actin, and localizations of EAAT1/2.ResultsFasudil and Y27632 increased [(3)H]-D-aspartate (D-Asp) uptake into astrocytes, and the action of Fasudil was time-dependent and concentration-related. The rapid stellation of astrocytes (glial fibrillary acidic protein immunocytochemistry) induced by Fasudil was accompanied by reduced phalloidin staining of F-actin and increased V(max) for [(3)H]-D-Asp uptake. Immunoblotting after biotinylation demonstrated that Fasudil increased the expression of EAAT1 and EAAT2 on the cell surface. Immunocytochemistry indicated that Fasudil induced prominent labelling of astrocytic processes by EAAT1/2.Conclusion and implicationsThese data show for the first time that ROCK plays a major role in determining the cell surface expression of EAAT1/2, providing new evidence for an association between transporter function and astrocytic phenotype. ROCK inhibitors, via the actin cytoskeleton, effect a consequent elevation of glutamate transporter function - this activity profile may contribute to their beneficial actions in neuropathologies.