{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:55:57Z","timestamp":1793678157460,"version":"4.5.1"},"reference-count":126,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Within a year after a spinal cord injury (SCI), 75% of individuals develop spasticity. While normal movement relies on the ability to adjust reflexes appropriately, and on reciprocal inhibition of antagonistic muscles, spastic individuals display hyperactive spinal reflexes and involuntary muscle co\u2010contractions. Current anti\u2010spastic medications can suppress uncontrolled movements, but by acting on GABAergic signalling, these medications lead to severe side\u2010effects and weakened muscle force, making them incompatible with activity\u2010based therapies. We have previously shown that pharmacologically enhancing activity of KCC2, a chloride cotransporter, reduces signs of spasticity in anaesthetized chronic SCI rats. Here, we examine the effect of enhancing KCC2 in awake animals, using a battery of tests assessing hyperreflexia in multiple reflex pathways required for normal movement as well as locomotor function. Sprague\u2010Dawley rats were implanted with chronic EMG electrodes bilaterally in ankle flexor and ankle extensor muscles and received a complete spinal transection at T12. Four weeks following SCI, the stretch reflex, the non\u2010nociceptive cutaneous reflex pathway, the flexor withdrawal reflex and the crossed\u2010extensor reflex pathway as well as locomotor function were evaluated before and after receiving the KCC2 enhancer, CLP290. Our results show that enhancing KCC2 activity normalizes reflex responses in multiple pathways and reduces muscle co\u2010contraction without weakening motor output, thereby improving stepping ability. This work reveals the substantial potential for KCC2 enhancers as a novel anti\u2010spastic treatment.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70084-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>After chronic spinal cord injury (SCI), the dysregulation of chloride homeostasis and subsequent decrease in spinal inhibition contributes to the development of spastic symptoms.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We previously showed that enhancing the activity of the chloride co\u2010transporter KCC2 after SCI decreases electrophysiological correlates of hyperreflexia and spasticity in deeply anaesthetized animals.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Here, we examine the effect of enhancing KCC2 activity in awake animals on the excitability of multiple spinal reflex pathways required for normal movement including locomotion.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We show that CLP290 decreases hyperreflexia, and reduces muscle co\u2010contraction without weakening motor output, thereby improving stepping ability.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our results suggest that KCC2 enhancers such as CLP290 have the potential to be used as an anti\u2010spastic treatment after SCI.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp287774","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T19:16:59Z","timestamp":1757013419000},"page":"5701-5721","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["KCC2 enhancers normalize reflex responses and improve locomotor function after chronic spinal cord injury"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9893-1334","authenticated-orcid":false,"given":"Jadwiga 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