Melissa L Masicampo1,2, Hong Qu Shan1, Victoria Xu1, Merritt Speagle1, Dwayne W Godwin1,2. 1. Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, USA. 2. Department of Physiology and Pharmacology, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, USA.
Abstract
AIMS: We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we investigated whether blockade of these calcium channels with the selective antagonist TTA-P2 also reduces alcohol-WD seizure. SHORT SUMMARY: The non-specific T-type calcium channel antagonist, ETX, is protective against alcohol-WD seizure. However, the mechanism of this effect is unclear. Here, we provide evidence that further suggests selective blockade of T-type calcium channels are protective against alcohol-WD seizure and WD-related mortality. METHODS: We used an intermittent ethanol exposure model to produce WD-induced hyperexcitability in DBA/2 J mice. Seizure severity was intensified with the chemoconvulsant pentylenetetrazole (PTZ). RESULTS: TTA-P2 (10 mg/kg) reduced seizure severity in mice undergoing alcohol WD with concurrent PTZ treatment (20 mg/kg). Moreover, TTA-P2 (20 and 40 mg/kg) was also protective against PTZ-induced (40 mg/kg) seizure and mortality. CONCLUSIONS: These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels.
AIMS: We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we investigated whether blockade of these calcium channels with the selective antagonist TTA-P2 also reduces alcohol-WD seizure. SHORT SUMMARY: The non-specific T-type calcium channel antagonist, ETX, is protective against alcohol-WD seizure. However, the mechanism of this effect is unclear. Here, we provide evidence that further suggests selective blockade of T-type calcium channels are protective against alcohol-WD seizure and WD-related mortality. METHODS: We used an intermittent ethanol exposure model to produce WD-induced hyperexcitability in DBA/2 J mice. Seizure severity was intensified with the chemoconvulsant pentylenetetrazole (PTZ). RESULTS: TTA-P2 (10 mg/kg) reduced seizure severity in mice undergoing alcohol WD with concurrent PTZ treatment (20 mg/kg). Moreover, TTA-P2 (20 and 40 mg/kg) was also protective against PTZ-induced (40 mg/kg) seizure and mortality. CONCLUSIONS: These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels.
Authors: Stuart D Greenhill; Nicola H Morgan; Peter V Massey; Gavin L Woodhall; Roland S G Jones Journal: Neuropharmacology Date: 2011-09-17 Impact factor: 5.250
Authors: N Leresche; H R Parri; G Erdemli; A Guyon; J P Turner; S R Williams; E Asprodini; V Crunelli Journal: J Neurosci Date: 1998-07-01 Impact factor: 6.167
Authors: Vahid Khalilzad Sharghi; Eric A Maltbie; Wen-Ju Pan; Shella D Keilholz; Kaundinya S Gopinath Journal: Front Neurosci Date: 2022-08-08 Impact factor: 5.152