title: HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats.
abstract: Clinical and experimental studies suggest that voltage-gated sodium channels (VGSCs) play a key role in the pathogenesis of neuropathic pain and that blocking agents against these channels can be potentially therapeutic. In the current study, we investigated whether a novel compound, (-)-2-Amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-propan-1-one(HYP-17), binds to VGSCs and evaluated its inhibitory effect on Na+currents of the rat dorsal root ganglia (DRG) sensory neurons and its analgesic effect on inflammatory and neuropathic pain. HYP-17 (10μM) reduced both the tetrodotoxin-sensitive (TTX-S) and the TTX-resistant (TTX-R) currents in DRG sensory neurons. However, neither the voltage-dependent activation curves nor the steady-state inactivation curves for TTX-S and TTX-R currents were changed by HYP-17. In rats injected with 5% formalin under the plantar surface of the hind paw, HYP-17 (10μg) significantly reduced both the early and late phase spontaneous pain behaviors. Systemic injection with HYP-17 (60mg/kg, i.p.) also significantly relieved the mechanical, cold, and warm allodynia induced by rat tail nerve injury. Furthermore, HYP-17 (60mg/kg, i.p.) significantly relieved the central neuropathic pain induced by spinal cord injury (SCI), and inhibited c-Fos expression in lumbar (L) 4-L5 spinal segments. Electrophysiological study showed that HYP-17 significantly attenuated the hyper-responsiveness of lumbar dorsal horn neurons. In addition, HYP-17 significantly reduced the levels of pp38MAPK and p-JNK in microglia and astrocytes, respectively, in the L4-L5 spinal dorsal horn. Therefore, our results indicate that HYP-17 has potential analgesic activities against nociceptive, inflammatory and neuropathic pain.
authors.affiliation: Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Jee Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Yoo Lim
authors.initials: YL
authors.lastname: Kam
authors.affiliation: School of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Jungae
authors.initials: J
authors.lastname: Oh
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, 14662, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, 14662, Republic of Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Han
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
authors.forename: Inchan
authors.initials: I
authors.lastname: Youn
authors.affiliation: School of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: hypark@ewha.ac.kr.
authors.forename: Hea-Young Park
authors.initials: HP
authors.lastname: Choo
authors.affiliation: Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: tyune@khu.ac.kr.
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Yune
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000700:Analgesics; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; C000622040:HYP-17 compound; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D061567:Voltage-Gated Sodium Channel Blockers; D013779:Tetrodotoxin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000409:Alanine
keywords: Astrocyte; Microglia; Neuropathic pain; Sodium channel inhibitor; Spinal cord injury; Tail nerve injury