TNFR1 upregulation mediates tolerance after brain ischemic preconditioning

Area of Science:

• Neuroscience
• Ischemic Stroke Research
• Cellular Signaling

Background:

• Ischemic preconditioning (IPC) confers resistance to severe ischemic injury (ischemic tolerance, IT).
• Tumor necrosis factor-alpha (TNF-alpha) and its processing enzyme, TACE, play a role in IPC.
• The precise mechanisms and signaling pathways underlying IT remain incompletely understood.

Purpose of the Study:

• To investigate the expression and localization of TNF receptors (TNFR) in ischemic tolerance.
• To elucidate the role of TNFR1 and downstream signaling pathways in IPC-induced neuroprotection.
• To explore the involvement of TACE, TNFR1, and NF-kappaB in the development of ischemic tolerance.

Main Methods:

• Focal ischemic preconditioning using temporary middle cerebral artery occlusion (tMCAO) in a rodent model.
• Induction of permanent MCAO 48 hours post-IPC to assess ischemic tolerance.
• Pharmacological inhibition of TACE (BB1101), TNFR1 (antisense oligodeoxynucleotide), and proteasome (lactacystin).
• Measurement of infarct volume and analysis of NF-kappaB activation.
• Immunohistochemical localization of TACE and TNFR1 in neurons.

Main Results:

• IPC significantly reduced infarct volume, confirming the development of ischemic tolerance.
• IPC induced neuronal upregulation of TNFR1, which was attenuated by the TACE inhibitor BB1101.
• Inhibition of TNFR1 expression via antisense oligodeoxynucleotide abolished the protective effect of IPC.
• Treatment with BB1101, TNFR1 antisense, or lactacystin blocked IPC-induced NF-kappaB activation.
• Immunohistochemistry confirmed neuronal expression of TACE and TNFR1.

Conclusions:

• Ischemic preconditioning leads to neuronal upregulation of TACE and TNFR1.
• The TACE/TNF-alpha/TNFR1/NF-kappaB signaling pathway is critically involved in mediating ischemic tolerance.
• Targeting this pathway holds potential for therapeutic strategies against ischemic stroke.