Introduction: Histamine has long been studied for its inflammatory activity. Several recent studies have also demonstrated that H3 receptor antagonists possess neuroprotective effect. However, the underlying mechanisms of the neuroprotective property of H3 receptor antagonists have not been fully investigated. Given that glutamate plays a pivotal role in neuroprotection, the goal of this study was to examine the presynaptic effect of H3 receptor antagonists on glutamate release and elucidate the underlying mechanisms.
Materials: Isolated nerve terminals (synaptosomes) purified from male Sprague-Dawley rat cerebral cortex were used to examine the effect of ciproxifan, an H3 antagonist, on glutamate release evoked by 4-aminopyridine (4-AP). Pharmacological activators and inhibitors of protein kinase cascades were used to investigate the possible downstream signaling pathway.
Results: Results showed that ciproxifan exhibited a concentration-dependent inhibition of 4-AP-evoked glutamate release. In addition, this inhibition was prevented by chelating the intrasynaptosomal Ca2+ ions and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. The inhibition of evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca2+ release. Inhibition of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) also prevented the inhibitory effect of ciproxifan on evoked glutamate release.
Conclusion: Our results suggest that ciproxifan inhibits glutamate release from rat cortical synaptosomes through the suppression of presynaptic voltage-dependent Ca2+ channels and both PKA and MAPK signaling cascades. These findings may delineate the possible neuroprotective mechanisms of H3 antagonists.

Ciproxifan, a histamine H3 receptor antagonist, suppresses depolarization-evoked glutamate release in rat cerebrocortical nerve terminals via protein kinase A and mitogen-activated protein kinase signaling pathways