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Cell death is a key feature of neurological diseases, including stroke and neurodegenerative disorders. Studies in a variety of ischemic/hypoxic mouse models demonstrate that poly(ADP-ribose) polymerase 1 (PARP-1)-dependent cell death, also named PARthanatos, plays a pivotal role in ischemic neuronal cell death and disease progress. PARthanatos has its unique triggers, processors, and executors that convey a highly orchestrated and programmed signaling cascade. In addition to its role in gene transcription, DNA damage repair, and energy homeostasis through PARylation of its various targets, PARP-1 activation in neuron and glia attributes to brain damage following ischemia/reperfusion. Pharmacological inhibition or genetic deletion of PARP-1 reduces infarct volume, eliminates inflammation, and improves recovery of neurological functions in stroke. Here, we reviewed the role of PARP-1 and PARthanatos in stroke and their therapeutic potential.

Galanin (GAL) plays key role in many pathophysiological processes, but its role in ischemic stroke remains unclear. Here, the models of 1 h middle cerebral artery occlusion (MCAO)/1-7 d reperfusion (R)-induced ischemic stroke and in vitro cell ischemia of 1 h oxygen-glucose deprivation (OGD)/24 h reoxygenation in primary cultured cortical neurons were used to explore GAL's effects and its underlying mechanisms. The results showed significant increases of GAL protein levels in the peri-infarct region (P) and infarct core (I) within 48 h R of MCAO mice (p

Interleukin (IL)-17A was reported to be involved in the development of post-ischemic stroke inflammatory response and functional recovery. However, the IL-17A dynamic changes in serum/cerebrospinal fluid (CSF) and its role in neuronal injury following ischemic stroke are unclear.In vivo ischemic stroke was induced by 1 h of middle cerebral artery occlusion (MCAO) and 6 h-7 d reperfusion (R) in mice, while in vitro stroke was induced by 1 h oxygen-glucose deprivation (OGD)/24 h reoxygenation (R) in cultured cortical neurons. Enzyme-linked immunosorbent assay (ELISA) and double-labeled immunofluorescence of IL-17A with neuron (NeuN), astrocyte (GFAP) and microglia (Iba-1)-specific markers were used to determine the IL-17A levels in serum/CSF and neural cell type.The ELISA results showed that IL-17A significantly increased both in peri-infarct region (p 0.001) and CSF (p 0.05) following 1 h MCAO/R 12 h. The levels of IL-17A in serum increased at R 1 d (p 0.05) and peaked at R 3 d (p 0.001) after 1 h MCAO. Immunofluorescent staining demonstrated that IL-17A co-localized with GFAP in peri-infarct regions. In addition, recombinant rIL-17A could aggravate ischemic injuries at dose-dependent manner in 1 h OGD/R 24 h-treated neurons companying with the increase of IL-17A receptor il-17RA mRNA (p 0.001) and IL-17R protein levels.We firstly reported astrocytic IL-17A peaks in CSF within 12 h and in serum at 3 d reperfusion after ischemic stroke. IL-17A may exaggerate neuronal injuries through its receptor IL-17R at early stage of ischemic stroke.

We have reported that neuron-specific conventional protein kinase C (cPKC)γ is involved in the development of cerebral hypoxic preconditioning (HPC) and the neuroprotection against ischemic injuries, but its molecular mechanism is unclear. In this study, the adult and postnatal 24 h C57BL/6J wild-type (cPKCγ+/+) and cPKCγ knockout (cPKCγ−/−) mice were respectively used to establish the models of middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo and oxygen-glucose deprivation (OGD)-treated primarily cultured cortical neurons as cell ischemia in vitro. The results showed that cPKCγ knockout could increase the infarct volume and neuronal cell loss in the peri-infarct region, and enhance the neurological deficits, the impaired coordination, and the reduced muscle strength of mice following 1 h MCAO/1–7 days reperfusion. Meanwhile, cPKCγ knockout significantly increased the conversion of LC3-I to LC3-II and beclin-1 protein expression, and resulted in more reductions in P-Akt, P-mTOR, and P-S6 phosphorylation levels in the peri-infarct region of mice with ischemic stroke. The autophagy inhibitor BafA1 could enhance or reduce neuronal cell loss in the peri-infarct region of cPKCγ+/+ and cPKCγ−/− mice after ischemic stroke. In addition, cPKCγ knockout and restoration could aggravate or alleviate OGD-induced neuronal ischemic injury in vitro through Akt-mTOR pathway-mediated autophagy. These results suggested that cPKCγ-modulated neuron-specific autophagy improves the neurological outcome of mice following ischemic stroke through the Akt-mTOR pathway, providing a potential therapeutic target for ischemic stroke.