MitoTEMPO modulates trigeminal activation and mitochondrial biogenesis in a nitroglycerin-induced migraine model.

Abstract

BACKGROUND: Migraine is a disabling neurovascular disorder in which neuroinflammation, trigeminal activation, and mitochondrial dysfunction play central roles. Mitochondria-targeted antioxidants such as mitoTEMPO may modulate these mechanisms; however, their effects in nitroglycerin (NTG)-induced migraine models remain unclear. This study investigated the effects of mitoTEMPO on mitochondrial biogenesis, fusion-fission dynamics, trigeminal activation, and inflammation in the trigeminal ganglion in an NTG-induced migraine model. METHODS AND RESULTS: Thirty male Sprague-Dawley rats were allocated to control, mitoTEMPO (M), NTG, M + NTG (concomitant administration of mitoTEMPO with NTG), and NTG + M (delayed administration of mitoTEMPO following NTG exposure) groups (n = 6/group). Serum TNF-α levels were measured by ELISA; trigeminal c-Fos, mitofusin-1 (Mfn1), nuclear respiratory factor (NRF1), and mitochondrial transcription factor A (TFAM) protein levels were assessed by Western blot, while NADH-ubiquinone oxidoreductase chain 1 (ND1), TFAM, NRF1, Mfn1, and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) mRNA expressions were analyzed by RT-PCR. NTG administration significantly increased serum TNF-α levels and trigeminal c-Fos expression, confirming neuroinflammation and nociceptive activation. Concomitant mitoTEMPO administration attenuated c-Fos expression, whereas delayed administration had no effect, indicating a timing-dependent response. Compared with the NTG group, mitoTEMPO-treated NTG groups exhibited higher Mfn1, NRF1, and TFAM protein levels. At the transcriptional level, no differences were observed in ND1, TFAM, or NRF1 expression; however, Mfn1 mRNA was increased in the NTG group, and PGC-1α expression was significantly upregulated in the NTG + M group, consistent with a delayed mitochondrial biogenesis response. CONCLUSIONS: These findings suggest that NTG induces trigeminal activation and inflammation with limited acute effects on mitochondrial biogenesis, while mitoTEMPO modulates these processes in a phase-dependent manner.