Histamine protects against NMDA‐induced necrosis in cultured cortical neurons through H₂ receptor/cyclic AMP/protein kinase A and H₃ receptor/GABA release pathways

Abstract

Using histamine and the H 3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine reversed the neurotoxicity in a concentration-dependent manner and showed peak protection at a concentration of 10 )7 M. This protection was antagonized by the H 2 receptor antagonists cimetidine and zolantidine but not by the H 1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H 2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8-Bromo-cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine and the cAMP-dependent protein kinase inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDAinduced excitotoxicity, which was reversed by the H 3 receptor agonist (R)-a-methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABA A receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDAstimulated samples. These results indicate that not only the H 2 receptor/cAMP/cAMP-dependent protein kinase pathway but also the H 3 receptor/GABA release pathway can attenuate NMDA-induced neurotoxicity.

The effects of thioperamide on extracellular levels of glutamate and GABA in the rat prefrontal cortex

“…Administration of thioperamide, at doses previously shown to result in high occupancy of the H3 receptor (Mochizuki et al 1996) had no affect on basal levels of GABA or glutamate. This contrasts a previous report showing increases in GABA and glutamate release (Dai et al 2006), and may reflect the different methods used (in vitro release from cultured cerebrocortical neurons obtained from rat pups in the previous study). However, it should be noted that a nonsignificant increase in GABA was found (28% above baseline in the 20 mg/kg thioperamide group, p=0.4-0.5).…”

“…In the hypothalamus, blockade of the H3 receptor with thioperamide enhances GABA release (Yamamoto et al 1997), while H3 receptors have been postulated to presynaptically inhibit glutamate release in the striatum, basolateral amygdala, and the dentate gyrus (Brown and Reymann 1996;Jiang et al 2005;Molina-Hernandez et al 2001). In cultured cerebrocortical neurons, it has been shown that application of an H3R antagonist results in a time-dependent increase in both GABA and glutamate (Dai et al 2006). The purpose of the present study was to determine the in vivo regulation of GABA and glutamate release in the prefrontal cortex by H3 receptors using the H3R antagonist thioperamide and in vivo microdialysis.…”

Role of histamine in brain protection in surgical brain injury in mice

“…These effects of thioperamide suggest that the drug may have mild pro-apoptotic effects. However, thioperamide may also facilitate GABAergic transmission (GABA is an inhibitory neurotransmitter), and thereby may be neuroprotective by simply reducing brain activity (Dai et al, 2006). The molecular events that occur as a result of combined thioperamide and L-histidine treatment remain unclear.…”

Carnosine Protects Against Aβ42-induced Neurotoxicity in Differentiated Rat PC12 Cells

“…The mobile phase (0.1 M Na 2 HPO 4 in 22% methanol and 13% acetonitrile, pH 6.8 with H 3 PO 4 ) was filtered through a 0.22 lm filter (Millipore, Bedford MA, USA) and degassed Cell Mol Neurobiol (2008) 28:307-316 309 before pumping at a flow rate of 0.75 ml/min. The samples were derivatized according to previous methods (Donzanti et al 1988;Jin et al 2005;Dai et al 2006) with minor modifications. The derivatization stock reagent consisted of 27 mg of o-phthalaldehyde (OPA, Pickering, Mountain View, CA, USA) dissolved in 1 ml of MeOH with 10 mg thiofluor (Pickering, Mountain View, CA, USA) and 9 ml 0.1 M sodium tetraborate (pH 9.3).…”