Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction

Jonah L. Wirt; Luana Assis Ferreira; Carlos Henrique Alves Jesus; Taylor J. Woodward; Idaira Oliva; Zhili Xu; Jonathon D. Crystal; Robert H. Pepin; Richard B. Silverman; Andrea G. Hohmann

doi:10.1073/pnas.2318833121

Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction

Jonah L. Wirt, Luana Assis Ferreira, Carlos Henrique Alves Jesus, Taylor J. Woodward, Idaira Oliva, Zhili Xu, Jonathon D. Crystal, Robert H. Pepin, Richard B. Silverman^*, Andrea G. Hohmann^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA’s degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund’s adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.

Original language	English (US)
Article number	e2318833121
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	122
Issue number	1
DOIs	https://doi.org/10.1073/pnas.2318833121
State	Published - Jan 7 2025

Funding

We thank NIH [Grants DA030604 (to R.B.S.), NS123057 (to R.B.S. with subcontract to A.G.H.), and DA047858 (to A.G.H.)] for the financial support of this research. J.L.W. and T.W. received support via T32DA024628 and the Harlan Research Scholars Program. T.W. received support as a Gill Graduate Research Fellow. A.G.H. acknowledges the generous donation of an Agilent 6495C triple quadrupole mass spectrometer (QQQ-MS) to the Indiana University Department of Chemistry\u2019s Mass Spectrometry Facility, by Agilent Technologies through their participation in the Indiana Center for Bioanalytical Metrology. We also acknowledge Shane Tichy and Karen Yannell of Agilent Technologies for the HILIC-Z LC method utilized in this study and for their efforts in familiarization with the new QQQ-MS system. We also acknowledge Emily Sizemore for technical assistance.

Keywords

chemotherapy-induced peripheral neuropathy
GABA aminotransferase
inflammatory pain
nonaddictive pain treatment
OV329

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.2318833121

Cite this

Wirt, J. L., Ferreira, L. A., Alves Jesus, C. H., Woodward, T. J., Oliva, I., Xu, Z., Crystal, J. D., Pepin, R. H., Silverman, R. B., & Hohmann, A. G. (2025). Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction. Proceedings of the National Academy of Sciences of the United States of America, 122(1), Article e2318833121. https://doi.org/10.1073/pnas.2318833121

@article{88bc20445b5c4a39a17164049d14b40c,

title = "Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction",

abstract = "Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA{\textquoteright}s degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund{\textquoteright}s adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.",

keywords = "chemotherapy-induced peripheral neuropathy, GABA aminotransferase, inflammatory pain, nonaddictive pain treatment, OV329",

author = "Wirt, {Jonah L.} and Ferreira, {Luana Assis} and {Alves Jesus}, {Carlos Henrique} and Woodward, {Taylor J.} and Idaira Oliva and Zhili Xu and Crystal, {Jonathon D.} and Pepin, {Robert H.} and Silverman, {Richard B.} and Hohmann, {Andrea G.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 the Author(s).Published by PNAS.",

year = "2025",

month = jan,

day = "7",

doi = "10.1073/pnas.2318833121",

language = "English (US)",

volume = "122",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "1",

}

Wirt, JL, Ferreira, LA, Alves Jesus, CH, Woodward, TJ, Oliva, I, Xu, Z, Crystal, JD, Pepin, RH, Silverman, RB & Hohmann, AG 2025, 'Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction', Proceedings of the National Academy of Sciences of the United States of America, vol. 122, no. 1, e2318833121. https://doi.org/10.1073/pnas.2318833121

Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction. / Wirt, Jonah L.; Ferreira, Luana Assis; Alves Jesus, Carlos Henrique et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 122, No. 1, e2318833121, 07.01.2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction

AU - Wirt, Jonah L.

AU - Ferreira, Luana Assis

AU - Alves Jesus, Carlos Henrique

AU - Woodward, Taylor J.

AU - Oliva, Idaira

AU - Xu, Zhili

AU - Crystal, Jonathon D.

AU - Pepin, Robert H.

AU - Silverman, Richard B.

AU - Hohmann, Andrea G.

PY - 2025/1/7

Y1 - 2025/1/7

N2 - Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA’s degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund’s adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.

AB - Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA’s degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund’s adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.

KW - chemotherapy-induced peripheral neuropathy

KW - GABA aminotransferase

KW - inflammatory pain

KW - nonaddictive pain treatment

KW - OV329

UR - http://www.scopus.com/inward/record.url?scp=85214441463&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85214441463&partnerID=8YFLogxK

U2 - 10.1073/pnas.2318833121

DO - 10.1073/pnas.2318833121

M3 - Article

C2 - 39793055

AN - SCOPUS:85214441463

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 1

M1 - e2318833121

ER -

Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this