Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein

So when you know you are going to have a stroke get this pretreatment. Plan ahead.
http://journal.frontiersin.org/article/10.3389/fneur.2017.00256/full?

Rui-Xin Yang^1†, Jie Lei^1†, Bo-Dong Wang¹, Da-Yun Feng¹, Lu Huang¹, Yu-Qian Li¹, Tao Li², Gang Zhu¹, Chen Li¹, Fang-Fang Lu¹, Tie-Jian Nie¹, Guo-Dong Gao¹* and Li Gao¹*

• ¹Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
• ²Research Center of Traditional Chinese Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, China

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Introduction

Cerebral stroke is an important and tragic event that ranks as the second cause of death in the population. The number of incident strokes and stroke-related deaths has remained progressively increased in the past two decades (1). Cerebral stroke is defined as the sudden onset of loss of focal neurological function due to infarction or hemorrhage in the relevant part of the central nerve system, and ischemic stroke accounts for 70% of all stroke incidents (2). The best treatment for ischemic stroke is timely recanalization of the responsible artery followed by revascularization of the relevant area of the brain to salvage the peri-infarct neurons (3); however, ischemic/reperfusion (I/R) injury reduces the curative effect of this specific treatment. Therefore, to identify an efficient way to prevent I/R injury is essential for stroke patients to have a better outcome.

Cerebral I/R injury is a complex process that involves several mechanisms, including three major pathways in neurons: excitotoxicity, oxidative stress, and inflammation (4). Mitochondria play a key role in these pathways, both through ATP generation failure and as a key mediator in cell death pathways (5). In addition, I/R injury leads to mitochondrial dysfunction, which leads to oxidative stress and apoptosis (6). Thus, targeting mitochondria may be a potential therapy to reduce I/R injury.

DJ-1 is one of the causative genes associated with a familial form of Parkinson’s disease and has recently been proven to be a mitochondrial protector in I/R injury in the heart (7, 8). DJ-1 is critical for mitochondrial function, and the loss of DJ-1 causes mitochondrial fragmentation and dysfunction (9, 10). Hence, maintaining the expression and function of DJ-1 might be a promising way to protect mitochondrial function and further relieve I/R injury.

Sodium phenylbutyrate (SPB) is a small molecule (chemical structure shown in Figure 1A) that inhibits histone deacetylase activities and promotes the transcription of several genes, including that of DJ-1, in a Parkinson’s disease model (11). In this study, we investigated whether SPB exerts neuroprotection against I/R injury both in cell and animal models and explored the mechanisms underlying this protective effect.

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