Perampanel ameliorates nitroglycerin-induced migraine through inhibition of the cAMP/PKA/CREB signaling pathway in the trigeminal ganglion in rats

Abstract

Background Perampanel, a highly selective glutamate AMPA receptor antagonist, is widely used to treat epilepsy. Since the existence of common pathophysiological features between epilepsy and migraine, the aim of this study was to investigate whether perampanel could exert an antimigraine effect. Methods Nitroglycerin (NTG) was used to induce a migraine model in rats, and the model animals were pretreatment with 50 μg/kg and 100 μg/kg perampanel. The expression of pituitary adenylate-cyclase-activating polypeptide (PACAP) was quantified by western blot and quantitative real-time PCR in the trigeminal ganglion, and rat-specific enzyme-linked immunosorbent assay in serum. Western blot was also conducted to explore the effects of perampanel treatment on the phospholipase C (PLC)/protein kinase C (PKC) and protein kinase A (PKA)/cAMP-responsive-element-binding protein (CREB) signaling pathways. Moreover, the cAMP/PKA/CREB-dependent mechanism was evaluated via in vitro stimulation of hippocampal neurons. The cells were treated with perampanel, antagonists and agonists for 24 hours and cell lysates were prepared for western blot analysis. Results Perampanel treatment notably increased the mechanical withdrawal threshold and decreased head grooming and light-aversive behaviors in NTG-treated rats. It also decreased PACAP expression and affected cAMP/PKA/CREB signaling pathway. However, PLC/PKC signaling pathway may not be involved in this treatment. In in vitro studies, perampanel notably decreased PACAP expression by inhibiting cAMP/PKA/CREB signaling pathway. Conclusions This study shows that perampanel inhibits the migraine-like pain response and that this beneficial effect might be attributable to regulation of the cAMP/PKA/CREB signaling pathway.

A role of NLRP3 and MMP9 in migraine progression: a systematic review of translational study

“…These studies suggest that targeting these pathways could offer therapeutic benefits for migraine patients. Various pharmacological agents are explored across the studies, including natural compounds ( 58 , 65 ), traditional Chinese medicines ( 59 , 66 ), and novel drugs ( 62 , 67 ). These interventions aim to modulate molecular targets associated with migraine pathogenesis, highlighting the potential of diverse treatment modalities.…”

Effects of the AMPAr antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload

“…Despite the signi cant results, publications that studied the effect of PER on the phosphorylation of GluA1 receptors are scarce and inconclusive. A recent study by Zhai et al (2023), evaluated the effect of the drug on the expression of PKC (protein that phosphorylates GluA1) and phosphorylation of GluA1, trying to explain the effect of PER on migraine, through the expression of PKC and other enzymes, without nding a clear correlation [49]. Kim et al (2019), found that PER in uences the phosphorylation of GluA1 depending on the exposure time, in the same way that it alters the expression of several enzymes that phosphorylate the GluA1 subunit, such as PKC and CAMKII [50].…”