PURPOSE: The h current (Ih) is an inwardly mixed cationic conductance activated by membrane hyperpolarization and distributed predominantly in the apical dendrites of hippocampal pyramidal neurons. To verify a hypothesis that an anomalous hyperpolarization generates an abnormal excitation by way of Ih channels, we examined the effects of Ih blockers (CsCl and ZD7288) on electrically induced paroxysmal discharges (PADs). METHODS: Fifty-three adult male rabbits were used. We measured the PAD threshold elicited by stimulation to the apical dendritic layer of the hippocampal CA1 region before and after injecting 50 microl of each Ih blocker or saline extracellularly into the same region. RESULTS: In Ih blocker injection groups (n = 26), we obtained a significant increase in PAD threshold (1 mM CsCl: 163%, p < 0.01; 10 mM CsCl: 265%, p < 0.01; 100 mM CsCl: 199%, p < 0.01; 100 microM ZD7288: 192%, p < 0.05; 1 mM ZD7288: 246%, p < 0.05). Conversely, we did not obtain the increase in PAD threshold in a saline injection group (n = 10, 107%). The magnitude as well as duration of the effect had a tendency to depend on concentration of Ih blockers, although a saturated or declining tendency was observed with the 100 mM CsCl injection. CONCLUSIONS: We concluded that Ih channels might contribute to hippocampal epileptiform discharges in vivo. Our hypothesis for epileptogenesis demonstrated in the present experiment offers an idea to develop a new type of antiepileptic drug based on Ih blockers for the treatment of epileptic disorders refractory to current medications.
PURPOSE: The h current (Ih) is an inwardly mixed cationic conductance activated by membrane hyperpolarization and distributed predominantly in the apical dendrites of hippocampal pyramidal neurons. To verify a hypothesis that an anomalous hyperpolarization generates an abnormal excitation by way of Ih channels, we examined the effects of Ih blockers (CsCl and ZD7288) on electrically induced paroxysmal discharges (PADs). METHODS: Fifty-three adult male rabbits were used. We measured the PAD threshold elicited by stimulation to the apical dendritic layer of the hippocampal CA1 region before and after injecting 50 microl of each Ih blocker or saline extracellularly into the same region. RESULTS: In Ih blocker injection groups (n = 26), we obtained a significant increase in PAD threshold (1 mM CsCl: 163%, p < 0.01; 10 mM CsCl: 265%, p < 0.01; 100 mM CsCl: 199%, p < 0.01; 100 microM ZD7288: 192%, p < 0.05; 1 mM ZD7288: 246%, p < 0.05). Conversely, we did not obtain the increase in PAD threshold in a saline injection group (n = 10, 107%). The magnitude as well as duration of the effect had a tendency to depend on concentration of Ih blockers, although a saturated or declining tendency was observed with the 100 mM CsCl injection. CONCLUSIONS: We concluded that Ih channels might contribute to hippocampal epileptiform discharges in vivo. Our hypothesis for epileptogenesis demonstrated in the present experiment offers an idea to develop a new type of antiepileptic drug based on Ih blockers for the treatment of epileptic disorders refractory to current medications.
Authors: Qays Kharouf; A Marie Phillips; Lauren E Bleakley; Emma Morrisroe; Julia Oyrer; Linghan Jia; Andreas Ludwig; Liang Jin; Joseph A Nicolazzo; Elisabetta Cerbai; M Novella Romanelli; Steven Petrou; Christopher A Reid Journal: Br J Pharmacol Date: 2020-06-17 Impact factor: 8.739
Authors: Han-Shen Tae; Kelly M Smith; A Marie Phillips; Kieran A Boyle; Melody Li; Ian C Forster; Robert J Hatch; Robert Richardson; David I Hughes; Brett A Graham; Steven Petrou; Christopher A Reid Journal: Front Pharmacol Date: 2017-08-21 Impact factor: 5.810