Abstract
ABSTRACTGastrodin (GAS) is a predominant bioactive constituent of the Chinese herbal medicine Tianma (Gastrodia elata Blume). Many authors have reported GAS has the beneficial effect on diverse diseases of the CNS, including epilepsy, Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia. Here, we report GAS exhibited a robust neuroprotective effect in an Sprague-Dawley rat model of stroke (transient middle cerebral artery occlusion, tMCAO), and show that the underlying molecular mechanism involves its protective effect against Zn2+-toxicity and its anti-oxidative effects in astrocytes. Intraperitoneal administration of GAS (40 mg/kg) after MCAO reduced mean infarct volume to 30.1 ± 5.9% of that of MCAO controls and this neuroprotective effect was accompanied by neurological function recoveries which was measured using modified neurological severity score (mNSS). Interestingly, GAS induced up-regulation and nuclear translocation of Nrf2, and subsequently increased the expressions of anti-oxidative genes, such as, HO-1 and GCLM, in astrocytes. Furthermore, GAS co- or pre-treatment markedly suppressed Zn2+-induced cell death caused by excessive ROS production and PARP-1 induction. We found that GAS suppressed p67 expression and PAR formation in astrocytes, which might underlie the anti- Zn2+-toxicity and anti-oxidative effects of GAS in astrocytes. These findings indicate GAS protects astrocytes from Zn2+-induced toxicity and oxidative stress and these effects contribute to its neuroprotective effects in the postischemic brain.
Highlights
Gastrodin (GAS) is the main phenolic compound derived from the roots of Gastrodia elata Blume, which has been used in East Asia to treat epilepsy, paralysis, vertigo, headache, and convulsions (Park et al 2011)
We investigated whether GAS inhibits Zn2+-induced oxidative stress in astrocytes in the postischemic brain using a rat model and sought to identify the molecular mechanisms responsible for its protective effects, with respect to Nrf2 activation and the suppressions of NADPH oxidase, PARP-1 induction, and PAR formation in C6 astroglial cells
When 40 mg/kg of GAS was administered at 6 h postMCAO, mean infarct volume reduced to 43.9 ± 9.6% (n = 4, p < 0.05) of that of treatment naïve MCAO controls (Figure. 1(a and b))
Summary
Gastrodin (GAS) is the main phenolic compound derived from the roots of Gastrodia elata Blume, which has been used in East Asia to treat epilepsy, paralysis, vertigo, headache, and convulsions (Park et al 2011). It has been reported that GAS exerted neuroprotective effects in rat model of cerebral ischemic injury (Liu et al 2016). GAS inhibited oxygenglucose deprivation (OGD)-induced calcium and nitric oxide increases in hippocampal neuron (Zeng et al 2006) and enhanced cell survival under hypoxic conditions by inhibiting excitotoxicity (Xu et al 2007). In LPS-stimulated microglial cells, GAS exerted anti-inflammatory effects by inhibiting the phosphorylations of IkB and mitogen-activated protein kinase (MAPK) (Dai et al 2011). Various molecular mechanisms have been proposed to explain the antioxidative effects of GAS, these include, attenuation of catalase reduction, increased superoxide dismutase (SOD) expression (Zhao et al 2012) and the translocation of Nrf (nuclear factor erythroid-2-related factor) (Wang et al 2014)
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