Ampakines stimulate phrenic motor output after cervical spinal cord injury

L. B. Wollman; K. A. Streeter; A. F. Fusco; E. J. Gonzalez-Rothi; M. S. Sandhu; J. J. Greer; D. D. Fuller

doi:10.1016/j.expneurol.2020.113465

Ampakines stimulate phrenic motor output after cervical spinal cord injury

L. B. Wollman, K. A. Streeter, A. F. Fusco, E. J. Gonzalez-Rothi, M. S. Sandhu, J. J. Greer, D. D. Fuller^*

^*Corresponding author for this work

Physical Medicine and Rehabilitation

Research output: Contribution to journal › Review article › peer-review

18 Scopus citations

Abstract

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors increases phrenic motor output. Ampakines are a class of drugs that are positive allosteric modulators of AMPA receptors. We hypothesized that 1) ampakines can stimulate phrenic activity after incomplete cervical spinal cord injury (SCI), and 2) pairing ampakines with brief hypoxia could enable sustained facilitation of phrenic bursting. Phrenic activity was recorded ipsilateral (IL) and contralateral (CL) to C2 spinal cord hemisection (C2Hx) in anesthetized adult rats. Two weeks after C2Hx, ampakine CX717 (15 mg/kg, i.v.) increased IL (61 ± 46% baseline, BL) and CL burst amplitude (47 ± 26%BL) in 8 of 8 rats. After 90 min, IL and CL bursting remained above baseline (BL) in 7 of 8 rats. Pairing ampakine with a single bout of acute hypoxia (5-min, arterial partial pressure of O₂ ~ 50 mmHg) had a variable impact on phrenic bursting, with some rats showing a large facilitation that exceeded the response of the ampakine alone group. At 8 weeks post-C2Hx, 7 of 8 rats increased IL (115 ± 117%BL) and CL burst amplitude (45 ± 27%BL) after ampakine. The IL burst amplitude remained above BL for 90-min in 7 of 8 rats; CL bursting remained elevated in 6 of 8 rats. The sustained impact of ampakine at 8 weeks was not enhanced by hypoxia exposure. Intravenous vehicle (10% 2-Hydroxypropyl-β-cyclodextrin) did not increase phrenic bursting at either time point. We conclude that ampakines effectively stimulate neural drive to the diaphragm after cervical SCI. Pairing ampakines with a single hypoxic exposure did not consistently enhance phrenic motor facilitation.

Original language	English (US)
Article number	113465
Journal	Experimental Neurology
Volume	334
DOIs	https://doi.org/10.1016/j.expneurol.2020.113465
State	Published - Dec 2020

Funding

This work was supported by funding from the National Institutes of Health , grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments. This work was supported by funding from the National Institutes of Health, grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments.

Keywords

Ampakine
Hypoxia
Neuroplasticity
Phrenic
Respiratory
Spinal cord injury

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

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10.1016/j.expneurol.2020.113465

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title = "Ampakines stimulate phrenic motor output after cervical spinal cord injury",

abstract = "Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors increases phrenic motor output. Ampakines are a class of drugs that are positive allosteric modulators of AMPA receptors. We hypothesized that 1) ampakines can stimulate phrenic activity after incomplete cervical spinal cord injury (SCI), and 2) pairing ampakines with brief hypoxia could enable sustained facilitation of phrenic bursting. Phrenic activity was recorded ipsilateral (IL) and contralateral (CL) to C2 spinal cord hemisection (C2Hx) in anesthetized adult rats. Two weeks after C2Hx, ampakine CX717 (15 mg/kg, i.v.) increased IL (61 ± 46% baseline, BL) and CL burst amplitude (47 ± 26%BL) in 8 of 8 rats. After 90 min, IL and CL bursting remained above baseline (BL) in 7 of 8 rats. Pairing ampakine with a single bout of acute hypoxia (5-min, arterial partial pressure of O2 ~ 50 mmHg) had a variable impact on phrenic bursting, with some rats showing a large facilitation that exceeded the response of the ampakine alone group. At 8 weeks post-C2Hx, 7 of 8 rats increased IL (115 ± 117%BL) and CL burst amplitude (45 ± 27%BL) after ampakine. The IL burst amplitude remained above BL for 90-min in 7 of 8 rats; CL bursting remained elevated in 6 of 8 rats. The sustained impact of ampakine at 8 weeks was not enhanced by hypoxia exposure. Intravenous vehicle (10% 2-Hydroxypropyl-β-cyclodextrin) did not increase phrenic bursting at either time point. We conclude that ampakines effectively stimulate neural drive to the diaphragm after cervical SCI. Pairing ampakines with a single hypoxic exposure did not consistently enhance phrenic motor facilitation.",

keywords = "Ampakine, Hypoxia, Neuroplasticity, Phrenic, Respiratory, Spinal cord injury",

author = "Wollman, {L. B.} and Streeter, {K. A.} and Fusco, {A. F.} and Gonzalez-Rothi, {E. J.} and Sandhu, {M. S.} and Greer, {J. J.} and Fuller, {D. D.}",

note = "Funding Information: This work was supported by funding from the National Institutes of Health , grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments. Funding Information: This work was supported by funding from the National Institutes of Health, grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments. Publisher Copyright: {\textcopyright} 2020",

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language = "English (US)",

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journal = "Experimental Neurology",

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T1 - Ampakines stimulate phrenic motor output after cervical spinal cord injury

AU - Wollman, L. B.

AU - Streeter, K. A.

AU - Fusco, A. F.

AU - Gonzalez-Rothi, E. J.

AU - Sandhu, M. S.

AU - Greer, J. J.

AU - Fuller, D. D.

N1 - Funding Information: This work was supported by funding from the National Institutes of Health , grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments. Funding Information: This work was supported by funding from the National Institutes of Health, grant numbers: 1T32HL134621-01A1 (LBW), K99 HL143207-01 (KS), F32NS095620-01 (KS), 1R01HL139708-01A1 (DDF). We are grateful to Dr. Arnold Lippa of RespireRx for providing the ampakine CX717 used in these experiments. Publisher Copyright: © 2020

PY - 2020/12

Y1 - 2020/12

N2 - Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors increases phrenic motor output. Ampakines are a class of drugs that are positive allosteric modulators of AMPA receptors. We hypothesized that 1) ampakines can stimulate phrenic activity after incomplete cervical spinal cord injury (SCI), and 2) pairing ampakines with brief hypoxia could enable sustained facilitation of phrenic bursting. Phrenic activity was recorded ipsilateral (IL) and contralateral (CL) to C2 spinal cord hemisection (C2Hx) in anesthetized adult rats. Two weeks after C2Hx, ampakine CX717 (15 mg/kg, i.v.) increased IL (61 ± 46% baseline, BL) and CL burst amplitude (47 ± 26%BL) in 8 of 8 rats. After 90 min, IL and CL bursting remained above baseline (BL) in 7 of 8 rats. Pairing ampakine with a single bout of acute hypoxia (5-min, arterial partial pressure of O2 ~ 50 mmHg) had a variable impact on phrenic bursting, with some rats showing a large facilitation that exceeded the response of the ampakine alone group. At 8 weeks post-C2Hx, 7 of 8 rats increased IL (115 ± 117%BL) and CL burst amplitude (45 ± 27%BL) after ampakine. The IL burst amplitude remained above BL for 90-min in 7 of 8 rats; CL bursting remained elevated in 6 of 8 rats. The sustained impact of ampakine at 8 weeks was not enhanced by hypoxia exposure. Intravenous vehicle (10% 2-Hydroxypropyl-β-cyclodextrin) did not increase phrenic bursting at either time point. We conclude that ampakines effectively stimulate neural drive to the diaphragm after cervical SCI. Pairing ampakines with a single hypoxic exposure did not consistently enhance phrenic motor facilitation.

AB - Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors increases phrenic motor output. Ampakines are a class of drugs that are positive allosteric modulators of AMPA receptors. We hypothesized that 1) ampakines can stimulate phrenic activity after incomplete cervical spinal cord injury (SCI), and 2) pairing ampakines with brief hypoxia could enable sustained facilitation of phrenic bursting. Phrenic activity was recorded ipsilateral (IL) and contralateral (CL) to C2 spinal cord hemisection (C2Hx) in anesthetized adult rats. Two weeks after C2Hx, ampakine CX717 (15 mg/kg, i.v.) increased IL (61 ± 46% baseline, BL) and CL burst amplitude (47 ± 26%BL) in 8 of 8 rats. After 90 min, IL and CL bursting remained above baseline (BL) in 7 of 8 rats. Pairing ampakine with a single bout of acute hypoxia (5-min, arterial partial pressure of O2 ~ 50 mmHg) had a variable impact on phrenic bursting, with some rats showing a large facilitation that exceeded the response of the ampakine alone group. At 8 weeks post-C2Hx, 7 of 8 rats increased IL (115 ± 117%BL) and CL burst amplitude (45 ± 27%BL) after ampakine. The IL burst amplitude remained above BL for 90-min in 7 of 8 rats; CL bursting remained elevated in 6 of 8 rats. The sustained impact of ampakine at 8 weeks was not enhanced by hypoxia exposure. Intravenous vehicle (10% 2-Hydroxypropyl-β-cyclodextrin) did not increase phrenic bursting at either time point. We conclude that ampakines effectively stimulate neural drive to the diaphragm after cervical SCI. Pairing ampakines with a single hypoxic exposure did not consistently enhance phrenic motor facilitation.

KW - Ampakine

KW - Hypoxia

KW - Neuroplasticity

KW - Phrenic

KW - Respiratory

KW - Spinal cord injury

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VL - 334

JO - Experimental Neurology

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Ampakines stimulate phrenic motor output after cervical spinal cord injury

Abstract

Funding

Keywords

ASJC Scopus subject areas

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