Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke

ABSTRACT

Introduction: Roles of autophagy/mitophagy activation in ischemic stroke remain controversial. To elucidate potential reasons, we analyze the factors responsible for divergent results in literatures. Reactive nitrogen species (RNS) are important cytotoxic factors in ischemic stroke. Herein, we particularly discuss the roles played by RNS in autophagy/mitophagy and ischemic brain injury.

Areas covered: Following factors should be considered in the studies on autophagy/mitophagy in ischemic stroke: (1) Protocols for administration of autophagy regulators including administration time points, routes and doses, etc.; (2) Specificity of autophagy regulators; (3) Animal models of cerebral ischemia with or without reperfusion. In the underlying mechanisms of autophagy/mitophagy, we particularly discuss the potential roles of RNS in mediating excessive autophagy/mitophagy during cerebral ischemia/reperfusion injury.

Expert opinion: Emphasis should be given to the following aspects in future studies: (1) Targeting RNS and related cellular signaling pathways in the regulation of autophagy/mitophagy might be a promising strategy for developing novel drugs as well as combined therapy for thrombolytic treatment to reach better outcomes for ischemic stroke; (2) Developing circulating plasma biomarkers linking RNS-mediated autophagy/mitophagy to the magnitude of ischemic brain injury will benefit for stroke treatment. Subsequently, RNS could be dominant therapeutic targets to regulate autophagy/mitophagy for ischemic stroke.

KEYWORDS:

• Autophagy
• ischemic stroke
• mitochondria
• mitophagy
• programmed cell death
• reactive nitrogen species

Article highlights

• Activated autophagy has double-edged roles in ischemic stroke. The beneficial or detrimental effects of activated autophagy on ischemic brain appear to be dependent on the experimental protocols with different intervening time points of autophagy, administration routes and doses of autophagy regulators and so forth.

• Reperfusion after ischemia appears to act as a critical turning point determining the roles of autophagy from neuroprotection to neurotoxicity via affecting programmed cell death.

• Mitophagy, as a selective autophagy, predominates in ischemic brain and also plays dual roles in ischemic stroke.

• RNS-mediated excessive autophagy/mitophagy could be an important cellular event contributing to cerebral I/R injury. Targeting RNS to regulate autophagy/mitophagy might shed new light on the therapies of ischemic stroke.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 31570855] and the Research Grants Council, University Grants Committee [grant number 776512M].