Intranasal empagliflozin modulates synaptic plasticity in migraine: Insights into calcium signaling and epigenetic regulation

Migraine is a primary headache disorder without a definite pathophysiology or satisfactory managing strategies. Recently, migraine is primarily a disorder of brain plasticity coupled with altered Ca²⁺ dynamics regulating gene activity and protein expression. Further, epigenetics provided new insight into migraine pathogenesis and therapeutic response elucidation. Sodium-glucose co-transporter-2-inhibitors (e.g., empagliflozin (EMPA)), are a class of antihyperglycemic agents that can cross the blood-brain-barrier to maintain glucose homeostasis. EMPA possesses myriad pharmacological actions with potential beneficial effects for migraine management. Thus, the current study aimed at exploring EMPA efficacy and mechanisms for treating migraine headache, emphasizing its role in synaptic plasticity and epigenetic mechanisms. Using an animal model of chronic migraine headache, the effect of oral (PO)/intranasal (IN) (brain-targeted)-EMPA versus Zolmitriptan (ZOL) on serum pain marker; Substance-P and migraine symptoms; pain, and photophobia were assessed biochemically and behaviorally. The influence on synaptic plasticity was evaluated by quantifying immunohistochemically stained synaptophysin in brain tissues and assessing calcium/calmodulin-activated-kinases (CaMKIIa)/ Camp-response-element-binding-protein (CREB)/calcitonin-gene-related-peptide (CGRP) or brain-derived-neurotrophic-factor (BDNF) pathways. Further, epigenetic modulation of migraine key genes was evaluated by determining HDAC6, CALCR, and MiR155-5p Moreover, serum glucose and amylin levels were appraised. Both EMPA-PO/IN significantly decreased serum levels of substance-P and pain symptoms, increased brain serotonin levels, synaptophysin expression, and modulated the CaMKIIa/CREB/CGRP/or BDNF pathway. In addition, EMPA-IN, but not ZOL, down-regulated HDAC6, CALCR, and MiR155-5p expressions. Further, unlike EMPA-IN, ZOL, and EMPA-PO demonstrated significant hypoglycemic effects. In conclusion, EMPA-IN shows potential as a novel therapeutic approach for managing migraine headaches by enhancing synaptic plasticity and modulating altered migraine-related epigenetic mechanisms.