Widespread brain parenchymal HMGB1 and NF-KB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice

Dehghani A., Phisonkunkasem T., Ozcan S. Y., DALKARA T., van den Maagdenberg A. M. J. M., Tolner E. A., ...Daha Fazla

NEUROBIOLOGY OF DISEASE, cilt.156, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 156
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.nbd.2021.105424
  • Dergi Adı: NEUROBIOLOGY OF DISEASE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Anahtar Kelimeler: HMGB1, NF-KB, NMDA receptor, Excitability, Neuron, Astrocyte, ENHANCED EXCITATORY TRANSMISSION, MOUSE MODELS, DEPRESSION, ACTIVATION, PATHOPHYSIOLOGY, SUSCEPTIBILITY, CORTEX
  • Hacettepe Üniversitesi Adresli: Evet

Özet

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-KB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-KB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-KB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved.