Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain...

Area of Science:

• Neuroscience
• Cellular Biology
• Biochemistry

Background:

• Cerebral ischemia triggers a cascade of cellular events, including proteostasis deregulation and neuronal death.
• Ischemia-induced autophagy is recognized, but the impact of thrombolysis on proteostasis remains unclear.

Purpose of the Study:

• To investigate the effect of tissue plasminogen activator (PLAT/tPA) mediated thrombolysis on autophagy and neuronal death.
• To elucidate the molecular mechanisms underlying PLAT/tPA's neuroprotective effects in cerebral ischemia.

Main Methods:

• Utilized in vitro models of hypoxia-reperfusion and an in vivo thromboembolic stroke model.
• Investigated the modulation of the PI3K-AKT-MTOR pathway and IGF1R activation.
• Analyzed PLAT/tPA's effect on IGFBP3 degradation and IGF1 bioavailability in vitro, in vivo, and in human stroke patients.

Main Results:

• Ischemia exacerbates deleterious neuronal autophagy.
• PLAT/tPA treatment decreases autophagy, conferring neuroprotection via PI3K-AKT-MTOR pathway modulation.
• Identified IGF1R as the key receptor, with PLAT/tPA increasing IGF1 bioavailability by degrading IGFBP3.

Conclusions:

• PLAT/tPA exerts neuroprotection in cerebral ischemia by reducing harmful autophagy.
• The mechanism involves the IGF1R pathway, enhanced by PLAT/tPA-mediated degradation of IGFBP3.
• Findings offer insights into therapeutic strategies for stroke.