nitroglycerin (nitroglycerin, Alza / Nitroderm / Nitroderm TTS)

Targeting neuronal FKBP5 attenuates mechanical allodynia by suppressing NF-κB-mediated neuroinflammation in an NTG-induced chronic migraine mouse model.

Peng Cheng C, Fan Tianhua T, Zhou Gang G, Zhao Min M et al.

Chronic migraine (CM) is a debilitating neurological disorder characterized by persistent trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and CM pathogenesis remains largely unknown. We used a nitroglycerin (NTG)-induced CM mouse model. Following RNA-sequencing (RNA-seq) of total RNA isolated from trigeminal nucleus caudalis (TNC) tissue lysates, target expression was validated via reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we used a neuron-specific CRISPR-Cas9 editing system for Fkbp5 knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the nuclear factor kappa B (NF-κB) inhibitor PDTC. Migraine-like behaviors were evaluated using von Frey filaments, coupled with biochemical analyses of NF-κB cascade activation and trigeminovascular neuroinflammation. RNA-seq, RT-qPCR, Western blotting, and immunofluorescence consistently confirmed a marked upregulation of Fkbp5 mRNA and FKBP5 protein in the TNC of NTG-treated mice, predominantly localized to neurons. Concurrently, significant microglial and astrocytic activation was observed in the TNC. Both neuron-specific Fkbp5 knockout and pharmacological inhibition with SAFit2 significantly attenuated NTG-induced periorbital and hind paw mechanical allodynia. Furthermore, FKBP5 deficiency blunted the NTG-triggered phosphorylation of p65 and IκBα, effectively suppressing the downstream release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the upregulation of calcitonin gene-related peptide (CGRP) and c-Fos. Crucially, targeted blockade of the NF-κB cascade with PDTC recapitulated the protective behavioral and biochemical effects of FKBP5 deficiency. We demonstrate that neuronal FKBP5 is significantly associated with CM pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for CM.

The Effect of Pharmacological and Non-Pharmacological Interventions on Headaches Induced by Intravenous Nitroglycerin Infusion: A Systematic Review.

Ahmadi Fatemeh F, Bagheri Nesami Masoumeh M, Abedinpour Mobina M

Nitroglycerin is a rapid-acting vasodilator commonly used as a first-line agent for the treatment of angina. Some patients receiving intravenous nitroglycerin infusion experience headaches as a side effect. Pain management is a critical priority for these patients. Therefore, this study aimed to determine the effect of pharmacological and non-pharmacological interventions on headaches induced by nitroglycerin infusion. This systematic review was conducted by searching the databases of SID, Magiran, Irandoc, Civilica, Science Direct, Web of Science, PubMed, Scopus, ProQuest, World Health Organization (WHO) and US Food and Drug Administration (FDA) and Google Scholar using the keywords "Nitroglycerin", "Glyceryl trinitrate", "Headache", "Cephalgia", "Cephalodynia", "Interventions" and "Infusion". After removing duplicates, studies were first screened based on inclusion and exclusion criteria, and their quality was then assessed. Finally, a total of 13 studies were entered into the systematic review. The total number of participants in all studies included in the review was 566 individuals aged 18 years and older. Eight studies (61.5%) addressed pharmacological interventions, and five studies (38.5%) addressed non-pharmacological interventions. The review of studies indicated that the use of cold compresses on the forehead, lavender essential oil aromatherapy, foot reflexology, sodium valproate, sumatriptan, and prednisone have proven to be effective treatments for headaches induced by nitroglycerin infusion; their use is recommended in the order mentioned for alleviating nitroglycerin-induced headaches. The use of cold compresses on the forehead, lavender essential oil aromatherapy, foot reflexology, sodium valproate, sumatriptan, and prednisone positively impacted the reduction of headaches induced by nitroglycerin infusion.

Transcranial Photobiomodulation Attenuates Neurogenic Inflammation and Sensory Hypersensitivity in a Nitroglycerin-Induced Migraine Model: Toward a Nonpharmacological Therapy.

Kazmi Sareh S, Vatandoust Seyed Mahdi SM, Athari Seyed Zanyar SZ, Ebrahimian Asal A et al.

Migraine is a debilitating neurological condition, characterized by headache, photophobia, and heightened mechanical/thermal sensitivity. Current pharmacological therapies often lead to incomplete relief and adverse effects, necessitating the use of noninvasive alternatives. This study evaluated transcranial photobiomodulation (PBM) in a nitroglycerin (NTG)-induced migraine model in male mice. Mice were assigned to Sham, NTG, NTG + Sumatriptan (SUMA; 600 µg/kg, s.c.), NTG + PBM, and NTG + PBM + SUMA groups. Over 9 days, NTG (5 mg/kg) was injected intraperitoneally every other day to develop an animal model of chronic migraine. The PBM protocol involved daily irradiation (810 nm) on the occipital bone of the head for 5 s over 9 days. The animals underwent behavioral testing for photophobia, mechanical allodynia, and thermal sensitivity. The trigeminal nucleus caudalis (TNC) was assessed for miR-155 expression by real-time PCR and protein expression of phospho-NF-κB, IL-1β, transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), calcitonin gene-related peptide (CGRP), c-Fos, and pituitary adenylate cyclase-activating polypeptide (PACAP) using immunoblotting. Behavioral assessment revealed that PBM significantly reduced head scratching and improved exploratory activity, decreased light aversion, reversed periorbital/hindpaw mechanical allodynia, and prolonged thermal withdrawal latency compared to the NTG group. Moreover, PBM downregulated miR-155 expression and decreased levels of inflammatory mediators and migraine-associated neuropeptides in the TNC. Notably, combined PBM and SUMA treatment resulted in improvements in behavioral and molecular outcomes compared to either treatment alone. These results indicate that PBM inhibited migraine-like behaviors and decreased the expression of numerous molecular markers that are linked to neuroinflammation and trigeminal activation in the TNC. These findings establish a foundation for additional research on transcranial PBM as a noninvasive method for modulating migraine-related behavioral responses.

Editorial expression of concern: Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice.

Casili Giovanna G, Lanza Marika M, Filippone Alessia A, Campolo Michela M et al.