Kortikal Yayılan Depresyonun Tetiklediği Nöroinflamasyonun Çözülmesi ve Bunun Migren Baş Ağrısı Patofizyolojisindeki Yeri

Abstract

Migraine is a common disorder which manifests itself as severe headache. Migraine pathophysiology needs deeper understanding in order to develop more effective treatments. Cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura. The idea that "Migraine pain emerges as a result of CSD-triggered parenchymal and subsequent meningeal sterile inflammatory response" is increasingly accepted. Formation of the inflammasome complex in neurons by CSD, activation of caspase-1 and release of high-mobility group box 1 (HMGB1) are the key events that activate the pro-inflammatory NF-kappa B cascade in astrocytes. We hypothesized that the resolution of this sterile inflammation may have a role in the spontaneous cessation of migraine headache and tested this hypothesis in male Swiss albino mice brain after single CSD introduced by pinprick. HMGB1 was found to be released immediately from the nuclei of 23±3.0% of all cortical cells (n = 3), yet not replaced within 24 hours (26±1.8%; p=0.26, n=3). We showed that HMGB1 carrying exosomes were released from neurons and detectable in the peripheral blood. It was found that the neuronal caspase-1 activity began to decrease 3 hours after CSD (1, 3 and 5 hours after CSD, active enzyme ratio was 11±3.0%, 5±0.4 and 6±1.1%, respectively; p=0.08; n=3). In nonneuronal cells, NF-kappa B subunits cRel (effective in resolution phase) and p65 (proinflammatory) were immediately activated by CSD, and within 24 hours cRel activity increased and p65 activity tended to decrease (respectively, active cell ratios 24±2.5 and 36±3.0% for cRel, 25±2.1 and 21±3.6% for p65; n=3). I-kappa B was also observed to migrate to 33±4.6% of nonneuronal nuclei after CSD (p=0.002; n=3). In nonneuronal cells, inflammation triggered by CSD appears to be regulated by a concerted action of pro- and anti-inflammatory processes. Furthermore, in 31±3.2% of neuronal nuclei cRel was constitutively present, and preliminary data suggest that p65 and cRel activity in neurons might play a role in synaptic spine restoration after CSD. In conclusion, the inflammatory response triggered by CSD begins to terminate within 24 hours by fading of neuronal caspase-1 activity, and in astrocytes, by a complex process involving anti-inflammatory c-Rel and I-kappa B activity. Single cell transcriptomics are required for further cellular details.