Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy

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Abstract

We evaluated whether pharmacologically targeting T-type Ca2+ channels with Z944, a potent and selective antagonist, has disease-modifying effects in a model of temporal lobe epilepsy (TLE) that exhibits spontaneous recurrent seizures, and manifests behavioral and cognitive comorbidities commonly experienced by patients with this condition. Wistar rats underwent implantation of EEG electrodes and one week later 4 h of kainic acid-induced status epilepticus (SE). Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6). Treatments were delivered by continuous subcutaneous infusion for four weeks during which time continuous video-EEG was acquired. Four weeks after completion of treatment, the animals had two further weeks of continuous video-EEG monitoring to evaluate the effects of the different treatments. Behavioral tests were performed to evaluate anxiety, depression, and cognition. On the video-EEG recordings four-week post-treatment, the Z944 group manifest reduced number of seizures (0.01 ± 0.01seizures/day) compared to vehicle (0.8 ± 0.1) and levetiracetam (0.5 ± 0.1) treated animals (p < 0.0001). Post-SE+ vehicle rats showed elevated depressive-like behavior, and deficits in spatial learning and memory compared to sham+vehicle rats, and these behavioral deficits were significantly improved in post-SE rats treated with Z944 (p < 0.05, for all comparisons). The results of this study show that treatment with Z944 has a disease-modifying effects in the post-SE model of TLE, reducing seizures as well as comorbid depressive-like behavior and cognitive impairment. This indicates that pharmacologically targeting T-type Ca2+ channels may be an effective disease-modifying treatment for temporal lobe epilepsy.

Original languageEnglish
Number of pages11
JournalProgress in Neurobiology
DOIs
Publication statusAccepted/In press - 13 Aug 2019

Keywords

  • Acquired epilepsy
  • Disease modification
  • Epileptogenesis
  • Kainic acid
  • Post-status epilepticus

Cite this

@article{b118ad28dd5d4258a5b099f532f14986,
title = "Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy",
abstract = "We evaluated whether pharmacologically targeting T-type Ca2+ channels with Z944, a potent and selective antagonist, has disease-modifying effects in a model of temporal lobe epilepsy (TLE) that exhibits spontaneous recurrent seizures, and manifests behavioral and cognitive comorbidities commonly experienced by patients with this condition. Wistar rats underwent implantation of EEG electrodes and one week later 4 h of kainic acid-induced status epilepticus (SE). Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6). Treatments were delivered by continuous subcutaneous infusion for four weeks during which time continuous video-EEG was acquired. Four weeks after completion of treatment, the animals had two further weeks of continuous video-EEG monitoring to evaluate the effects of the different treatments. Behavioral tests were performed to evaluate anxiety, depression, and cognition. On the video-EEG recordings four-week post-treatment, the Z944 group manifest reduced number of seizures (0.01 ± 0.01seizures/day) compared to vehicle (0.8 ± 0.1) and levetiracetam (0.5 ± 0.1) treated animals (p < 0.0001). Post-SE+ vehicle rats showed elevated depressive-like behavior, and deficits in spatial learning and memory compared to sham+vehicle rats, and these behavioral deficits were significantly improved in post-SE rats treated with Z944 (p < 0.05, for all comparisons). The results of this study show that treatment with Z944 has a disease-modifying effects in the post-SE model of TLE, reducing seizures as well as comorbid depressive-like behavior and cognitive impairment. This indicates that pharmacologically targeting T-type Ca2+ channels may be an effective disease-modifying treatment for temporal lobe epilepsy.",
keywords = "Acquired epilepsy, Disease modification, Epileptogenesis, Kainic acid, Post-status epilepticus",
author = "Casillas-Espinosa, {Pablo M.} and Shultz, {Sandy R.} and Braine, {Emma L.} and Jones, {Nigel C.} and Snutch, {Terrance P.} and Powell, {Kim L.} and O'Brien, {Terence J.}",
year = "2019",
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doi = "10.1016/j.pneurobio.2019.101677",
language = "English",
journal = "Progress in Neurobiology",
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TY - JOUR

T1 - Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy

AU - Casillas-Espinosa, Pablo M.

AU - Shultz, Sandy R.

AU - Braine, Emma L.

AU - Jones, Nigel C.

AU - Snutch, Terrance P.

AU - Powell, Kim L.

AU - O'Brien, Terence J.

PY - 2019/8/13

Y1 - 2019/8/13

N2 - We evaluated whether pharmacologically targeting T-type Ca2+ channels with Z944, a potent and selective antagonist, has disease-modifying effects in a model of temporal lobe epilepsy (TLE) that exhibits spontaneous recurrent seizures, and manifests behavioral and cognitive comorbidities commonly experienced by patients with this condition. Wistar rats underwent implantation of EEG electrodes and one week later 4 h of kainic acid-induced status epilepticus (SE). Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6). Treatments were delivered by continuous subcutaneous infusion for four weeks during which time continuous video-EEG was acquired. Four weeks after completion of treatment, the animals had two further weeks of continuous video-EEG monitoring to evaluate the effects of the different treatments. Behavioral tests were performed to evaluate anxiety, depression, and cognition. On the video-EEG recordings four-week post-treatment, the Z944 group manifest reduced number of seizures (0.01 ± 0.01seizures/day) compared to vehicle (0.8 ± 0.1) and levetiracetam (0.5 ± 0.1) treated animals (p < 0.0001). Post-SE+ vehicle rats showed elevated depressive-like behavior, and deficits in spatial learning and memory compared to sham+vehicle rats, and these behavioral deficits were significantly improved in post-SE rats treated with Z944 (p < 0.05, for all comparisons). The results of this study show that treatment with Z944 has a disease-modifying effects in the post-SE model of TLE, reducing seizures as well as comorbid depressive-like behavior and cognitive impairment. This indicates that pharmacologically targeting T-type Ca2+ channels may be an effective disease-modifying treatment for temporal lobe epilepsy.

AB - We evaluated whether pharmacologically targeting T-type Ca2+ channels with Z944, a potent and selective antagonist, has disease-modifying effects in a model of temporal lobe epilepsy (TLE) that exhibits spontaneous recurrent seizures, and manifests behavioral and cognitive comorbidities commonly experienced by patients with this condition. Wistar rats underwent implantation of EEG electrodes and one week later 4 h of kainic acid-induced status epilepticus (SE). Animals were randomly assigned to one of 5 different groups: post-SE + Z944 (60 mg/kg/day, n = 8); post-SE + levetiracetam (200 mg/kg/day, n = 9); post-SE + vehicle (n = 8); sham + vehicle (n = 6) or sham + Z944 (60 mg/kg/day, n = 6). Treatments were delivered by continuous subcutaneous infusion for four weeks during which time continuous video-EEG was acquired. Four weeks after completion of treatment, the animals had two further weeks of continuous video-EEG monitoring to evaluate the effects of the different treatments. Behavioral tests were performed to evaluate anxiety, depression, and cognition. On the video-EEG recordings four-week post-treatment, the Z944 group manifest reduced number of seizures (0.01 ± 0.01seizures/day) compared to vehicle (0.8 ± 0.1) and levetiracetam (0.5 ± 0.1) treated animals (p < 0.0001). Post-SE+ vehicle rats showed elevated depressive-like behavior, and deficits in spatial learning and memory compared to sham+vehicle rats, and these behavioral deficits were significantly improved in post-SE rats treated with Z944 (p < 0.05, for all comparisons). The results of this study show that treatment with Z944 has a disease-modifying effects in the post-SE model of TLE, reducing seizures as well as comorbid depressive-like behavior and cognitive impairment. This indicates that pharmacologically targeting T-type Ca2+ channels may be an effective disease-modifying treatment for temporal lobe epilepsy.

KW - Acquired epilepsy

KW - Disease modification

KW - Epileptogenesis

KW - Kainic acid

KW - Post-status epilepticus

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DO - 10.1016/j.pneurobio.2019.101677

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JO - Progress in Neurobiology

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