Inhibition of the p‑SPAK/p‑NKCC1 signaling pathway protects the blood‑brain barrier and reduces neuronal apoptosis in a rat model of surgical brain injury.

Abstract

Surgical brain injury (SBI) can disrupt the function of the blood‑brain barrier (BBB), leading to brain edema and neurological dysfunction. Thus, protecting the BBB and mitigating cerebral edema are key factors in improving the neurological function and prognosis of patients with SBI. The inhibition of WNK lysine deficient protein kinase/STE20/SPS1‑related proline/alanine‑rich kinase (SPAK) signaling ameliorates cerebral edema, and this signaling pathway regulates the phosphorylation of the downstream Na+‑K+‑Cl‑ cotransporter 1 (NKCC1). Therefore, the purpose of the present study was to investigate the role of SPAK in SBI‑induced cerebral edema and to determine whether the SPAK/NKCC1 signaling pathway was involved in SBI via regulating phosphorylation. An SBI model was established in male Sprague‑Dawley rats, and the effects of SPAK on the regulation of the NKCC1 signaling pathway on BBB permeability and nerve cell apoptosis by western blotting analysis, immunofluorescence staining, TUNEL staining, Fluoro‑Jade C staining, and brain edema and nervous system scores. The results demonstrated that, compared with those in the sham group, phosphorylated (p)‑SPAK and p‑NKCC1 protein expression levels were significantly increased in the SBI model group. After inhibiting p‑SPAK, the expression level of p‑NKCC1, neuronal apoptosis and BBB permeability were significantly reduced in SBI model rats. Taken together, these findings suggested that SBI‑induced increases in p‑SPAK and p‑NKCC1 expression exacerbated post‑traumatic neural and BBB damage, which may be mediated via the ion‑transport‑induced regulation of cell edema.

• Authors: Yating Gong, Muyao Wu, Fan Gao, Mengying Shi, Haiping Gu, Rong Gao, Bao-Qi Dang, Gang Chen
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 24 Issue 4 (10 2021) ISSN: 1791-3004 [Electronic] Greece
• PMID: 34396440 (Publication Type: Journal Article)

Chemical References

• Protective Agents
• Slc12a2 protein, rat
• Solute Carrier Family 12, Member 2
• PAS domain kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Blood-Brain Barrier
• Brain
• Brain Edema (metabolism)
• Brain Injuries (metabolism)
• Disease Models, Animal
• Male
• Protective Agents (pharmacology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Solute Carrier Family 12, Member 2 (genetics, metabolism)