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Activation of cerebral peroxisome proliferator‐activated receptors γ (PPARγ) reduces neuronal damage in the substantia nigra after transient focal cerebral ischaemia in the rat
Author(s) -
Zuhayra M.,
Zhao Y.,
von Forstner C.,
Henze E.,
Gohlke P.,
Culman J.,
Lützen U.
Publication year - 2011
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/j.1365-2990.2011.01169.x
Subject(s) - pioglitazone , substantia nigra , neuroprotection , endocrinology , medicine , pars compacta , peroxisome proliferator activated receptor , glutamate receptor , neuroscience , biology , receptor , dopamine , dopaminergic , type 2 diabetes , diabetes mellitus
M. Zuhayra, Y. Zhao, C. von Forstner, E. Henze, P. Gohlke, J. Culman and U. Lützen (2011) Neuropathology and Applied Neurobiology 37, 738–752 Activation of cerebral peroxisome proliferator‐activated receptors γ (PPARγ) reduces neuronal damage in the substantia nigra after transient focal cerebral ischaemia in the rat Aim: The function of brain (neuronal) peroxisome proliferator‐activated receptor(s) γ (PPARγ) in the delayed degeneration and loss of neurones in the substantia nigra (SN) was studied in rats after transient occlusion of the middle cerebral artery (MCAO). Methods: The PPARγ agonist, pioglitazone, or vehicle was infused intracerebroventricularly over a 5‐day period before, during and 5 days after MCAO (90 min). The neuronal degeneration in the SN pars reticularis (SNr) and pars compacta (SNc), the analysis of the number of tyrosine hydroxylase‐immunoreactive (TH‐IR) neurones and the expression of the PPARγ in these neurones were studied by immunohistochemistry and immunofluorescence staining. The effects of PPARγ activation on excitotoxic and oxidative neuronal damage induced by glutamate and 6‐hydroxydopamine were investigated in primary cortical neurones expressing PPARγ. Results: Pioglitazone reduced the total and striatal infarct size, neuronal degeneration in both parts of the ipsilateral SN, the loss of TH‐IR neurones in the SNc and increased the number of PPARγ‐positive TH‐IR neurones. Pioglitazone protected primary cortical neurones against oxidative and excitotoxic damage, prevented the loss of neurites and supported the formation of synaptic networks in neurones exposed to glutamate or 6‐hydroxydopamine by a PPARγ‐dependent mechanism. Conclusions: Activation of cerebral PPARγ confers neuroprotection after ischaemic stroke by preventing both, neuronal damage within the peri‐infarct zone and delayed degeneration of neurones and neuronal death in areas remote from the site of ischaemic injury. Pioglitazone and other PPARγ agonists may be useful therapeutic agents to prevent progression of brain damage after cerebral ischaemia.