PINK1 activation by MTK458 ameliorates neurological impairments and pyroptosis after intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is often linked to severe neurological impairments, including cognitive deficits and anxiety-like behaviors. This study aimed to evaluate the therapeutic potential of PTEN-induced kinase 1 (PINK1), which is activated during ICH, as a target for mitigating these effects. C57/BL6 wild-type mice underwent ICH induction through an intrastriatal injection of autologous blood. The PINK1 activator, MTK458, was administered daily doses of 10-50 mg/kg starting one week before ICH induction and continuing for three days post-surgery. The modified neurological severity score (mNSS) was used to assess neurological deficits, while brain edema was measured through brain water content. The open field test and Y-maze test were used to evaluate anxiety-like behavior, and cognitive function respectively. The effects of ICH on cortical cell Pyroptosis, Parkin/PINK1-mediated Mitophagy, and the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome were analyzed via Western blotting, ELISA, and qRT-PCR. MTK458 effectively reduced brain water content in the basal ganglia, ipsilateral cortex, and cerebellum, with improvements in mNSS extending to 14 days post-injury. Additionally, MTK458 alleviated both neurological deficits and anxiety-like behavior in ICH mouse models. It also reversed ICH-induced cortical cell Pyroptosis by promoting Parkin/PINK1-mediated Mitophagy and inhibiting NLRP3 inflammasome activation, as well as the expression of IL-1β and IL-18. These results suggest that MTK458 effectively reduces neurological impairments, brain edema, and anxiety-related behaviors in mice following ICH, highlighting PINK1 activation as a promising therapeutic strategy for ICH-induced neurological deficits.

Intracerebral hemorrhage; MTK458; Mitophagy; Neurological impairments; PINK1; Pyroptosis.