Activation of cerebral peroxisome proliferator-activated receptors gamma(PPAR gamma) reduces neuronal damage in the substantia nigra after transient focal cerebral ischaemia in the rat

作者：Zuhayra M; Zhao Y; von Forstner C; Henze E; Gohlke P; Culman J^*; Luetzen U

来源：Neuropathology and Applied Neurobiology, 2011, 37(7): 738-752.

DOI：10.1111/j.1365-2990.2011.01169.x

• cerebral ischaemia
• neurodegeneration
• pioglitazone
• PPAR gamma
• rat
• substantia nigra

Aim: The function of brain (neuronal) peroxisome proliferator-activated receptor(s) gamma(PPAR gamma) 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 PPAR gamma 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 PPAR gamma in these neurones were studied by immunohistochemistry and immunofluorescence staining. The effects of PPAR gamma activation on excitotoxic and oxidative neuronal damage induced by glutamate and 6-hydroxydopamine were investigated in primary cortical neurones expressing PPAR gamma. 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 PPAR gamma-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 PPAR gamma-dependent mechanism. Conclusions: Activation of cerebral PPAR gamma 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 PPAR gamma agonists may be useful therapeutic agents to prevent progression of brain damage after cerebral ischaemia.

• 出版日期2011-12