INTRANASAL POLYHERBAL NANOEMULSION- BASED DRUG DELIVERY FOR BRAIN TARGETING: A PROMISING STRATEGY FOR MIGRAINE THERAPY

Migraine is a multifactorial neurovascular disorder involving activation of the trigeminovascular system, cortical spreading depression (CSD), neurogenic inflammation, and dysregulation of calcitonin gene related peptide (CGRP) signaling. Conventional oral and parenteral therapies are limited by brain penetration, first-pass metabolism, and systemic adverse effects. The review highlights a polyherbal nanoemulsion- based intranasal drug delivery system as a targeted and non-invasive strategy for migraine management. The intranasal route enables direct nose-to- brain transport through the olfactory and trigeminal neural pathways, facilitating rapid drug delivery to key brain regions while bypassing the blood brain barrier, minimizes systemic exposure, and enhances drug bioavailability. The proposed nanoemulsion incorporates three bioactive phytoconstituents: thymoquinone (Nigella sativa), withanolides (Withaniya somnifera), and menthol (Mentha piperita), which collectively target multiple interconnected migraine pathways. Thymoquinone exerts potent anti- inflammatory and antioxidant effects by downregulating nuclear factor-kappa B(NF-_KB), inhibiting pro-inflammatory cytokines (TNF-α, IL-6). Withanolides demonstrate neuroprotective and anti-stress activity by modulating the hypothalamic- pituitary-adrenal (HPA) axis, reducing cortisol levels, and preventing neuronal apoptosis through antioxidant enzyme upregulation. Menthol activates transient receptor potential melastatin-8 (TRPM8) channels, leading to analgesic effects via modulation of calcium influx and inhibition of trigeminal nociceptive signaling, thereby reducing CGRP release. Nanoemulsion systems enhance solubility, mucosal permeation, and nasal residence time, enabling efficient drug transport across the nasal epithelium. The nanoscale droplet size further supports neuronal uptake and intracellular delivery. Overall, the synergistic combination of these phytoconstituents offers a multi-targeted therapeutic approach addressing neuroinflammation, oxidative stress, and central sensitization. This strategy represents a promising platform for rapid, targeted, and effective migraine therapy with improved patient compliance and reduced systemic toxicity.