article · Drug Delivery and Translational Research
Abstract Conventional zolmitriptan (ZOL) has limited oral bioavailability, many adverse effects, and poor membrane penetrability that negatively influences its accessibility to its 5-HT 1B/1D receptor binding pocket, located transmemberanous. This work aimed at preparing transdermal ZOL-nanoformulation (niosomes) to surpass these limitations and to explore novel antimigraine mechanisms for ZOL via modulation of the epigenetically-altered chronification genes (RAMP-1, NPTX-2) or microRNAs and affecting the endocannabinoid CB-1/MAPK pathway. The prepared ZOL niosomes (F sp60/6−1:1 ) exhibited %EE of 57.28%, PS of 472.3 nm, PDI of 0.366, and ZP of -26 mV were cast into patch with content uniformity of 93.12%, maintained endurance after 200-times folding, no interaction between its components (FT-IR), a biphasic release pattern and good stability after storage at 4 °C for 6 months. In-vivo ZOL-patch application in rats with nitroglycerin-induced migraine showed significant management of migraine pain symptoms and photophobia assessed behaviorally, decreased brain levels of the trigeminal neuronal activation marker (c-fos), the migraine pain neurotransmitter (CGRP) and the serum levels of different migraine pain markers (substance P, nitric-oxide, and TNF-α). It also significantly decreased RAMP-1, NPTX-2, miR-382-5p, and CB-1/MAPK gene expression reflecting improved efficacy and brain receptors delivery to a much greater extent than conventional ZOL has done. Additionally, this nanoformulation significantly opposed migraine-induced platelet activation and hypercoagulable status in both central and peripheral circulations as evidenced by the significant decrease in adenosine diphosphate, thrombin, factor X, CD41, and Von-Willebrand factor levels assessed peripherally and centrally. TPF sp60/6−1:1 significantly improved ZOL efficacy and accessibility to brain-receptors to a much greater extent than conventional ZOL-solution. KeywordsEndocannabinoid receptors; Epigenetically-altered genes; Hemostatic pathways; Niosomal patch; Transdermal; Zolmitriptan Graphical abstract
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DOI: 10.1007/s13346-024-01731-6
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