{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:54:47Z","timestamp":1792079687072,"version":"4.4.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea (NRF)","doi-asserted-by":"publisher","award":["NRF-2022R1A2C1091868"],"award-info":[{"award-number":["NRF-2022R1A2C1091868"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>This study was designed to compare the effects of various doses of botulinum neurotoxin A (BoNT\/A) on nerve regeneration. Sixty-five six-week-old rats with sciatic nerve injury were randomly allocated to three experimental groups, a control group, and a sham group. The experimental groups received a single session of intraneural BoNT\/A (3.5, 7.0, or 14 U\/kg) injection immediately after nerve-crushing injury. The control group received normal intraneural saline injections after sciatic nerve injury. At three, six, and nine weeks after nerve damage, immunofluorescence staining, an ELISA, and toluidine blue staining was used to evaluate the regenerated nerves. Serial sciatic functional index analyses and electrophysiological tests were performed every week for nine weeks. A higher expression of GFAP, S100\u03b2, GAP43, NF200, BDNF, and NGF was seen in the 3.5 U\/kg and 7.0 U\/kg BoNT\/A groups. The average area and myelin thickness were significantly greater in the 3.5 U\/kg and 7.0 U\/kg BoNT\/A groups. The sciatic functional index and compound muscle action potential amplitudes exhibited similar trends. These findings indicate that the 3.5 U\/kg and 7.0 U\/kg BoNT\/A groups exhibited better nerve regeneration than the 14 U\/kg BoNT\/A and control group. As the 3.5 U\/kg and the 7.0 U\/kg BoNT\/A groups exhibited no statistical difference, we recommend using 3.5 U\/kg BoNT\/A for its cost-effectiveness.<\/jats:p>","DOI":"10.3390\/toxins15120691","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T05:47:30Z","timestamp":1702014450000},"page":"691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Comparison of the Effects of Botulinum Toxin Doses on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury"],"prefix":"10.3390","volume":"15","author":[{"given":"Seokjoon","family":"Hwang","sequence":"first","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-5006","authenticated-orcid":false,"given":"Minsu","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Heon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-woo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7755-435X","authenticated-orcid":false,"given":"Bum Sun","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyeun","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Dongguk University College of Medicine, Goyang 10326, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/(SICI)1097-4598(200006)23:6<863::AID-MUS4>3.0.CO;2-0","article-title":"Traumatic injury to peripheral nerves","volume":"23","author":"Robinson","year":"2000","journal-title":"Muscle Nerve Off. J. Am. Assoc. Electrodiagn. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/bmb\/ldr005","article-title":"Non-surgical therapies for peripheral nerve injury","volume":"100","author":"Delgado","year":"2011","journal-title":"Br. Med. Bull."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.jss.2021.02.016","article-title":"Effect of nimodipine and botulinum toxin A on peripheral nerve regeneration in rats: A pilot study","volume":"264","author":"Odorico","year":"2021","journal-title":"J. Surg. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1055\/s-2007-1006407","article-title":"Historical and basic science review: Past, present, and future of nerve repair","volume":"13","author":"Terzis","year":"1997","journal-title":"J. Reconstr. Microsurg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1089\/pho.2007.2093","article-title":"Laser phototherapy (780 nm), a new modality in treatment of long-term incomplete peripheral nerve injury: A randomized double-blind placebo-controlled study","volume":"25","author":"Rochkind","year":"2007","journal-title":"Photomed. Laser Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1589\/jpts.25.1067","article-title":"Effect of extracorporeal shock wave therapy on denervation atrophy and function caused by sciatic nerve injury","volume":"25","author":"Lee","year":"2013","journal-title":"J. Phys. Ther. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neuroscience.2017.07.011","article-title":"Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers","volume":"359","author":"Cobianchi","year":"2017","journal-title":"Neuroscience"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Luvisetto, S. (2022). Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells. Toxins, 14.","DOI":"10.3390\/toxins14100704"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Luvisetto, S. (2020). Botulinum Toxin and Neuronal Regeneration after Traumatic Injury of Central and Peripheral Nervous System. Toxins, 12.","DOI":"10.3390\/toxins12070434"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Seo, M., Lim, D., Kim, S., Kim, T., Kwon, B.S., and Nam, K. (2021). Effect of Botulinum Toxin Injection and Extracorporeal Shock Wave Therapy on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury. Toxins, 13.","DOI":"10.3390\/toxins13120879"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0165-3806(94)90047-7","article-title":"Botulinum A toxin stimulates neurite branching in nerve-muscle cocultures","volume":"79","author":"Bonner","year":"1994","journal-title":"Dev. Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chomiak, T., and Hu, B. (2009). What is the optimal value of the g-ratio for myelinated fibers in the rat CNS?. A theoretical approach. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007754"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0119","DOI":"10.2106\/JBJS.RVW.19.00119","article-title":"Botulinum toxin A injection in treatment of upper limb spasticity in children with cerebral palsy: A systematic review of randomized controlled trials","volume":"8","author":"Farag","year":"2020","journal-title":"JBJS Rev."},{"key":"ref_14","first-page":"CD001408","article-title":"Botulinum toxin type A in the treatment of lower limb spasticity in children with cerebral palsy","volume":"2019","author":"Blumetti","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Finocchiaro, A., Marinelli, S., De Angelis, F., Vacca, V., Luvisetto, S., and Pavone, F. (2018). Botulinum Toxin B Affects Neuropathic Pain but Not Functional Recovery after Peripheral Nerve Injury in a Mouse Model. Toxins, 10.","DOI":"10.3390\/toxins10030128"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1177\/1545968318790020","article-title":"Botulinum Toxin Conditioning Enhances Motor Axon Regeneration in Mouse and Human Preclinical Models","volume":"32","author":"Franz","year":"2018","journal-title":"Neurorehabilit. Neural Repair"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Adler, M., Pellett, S., Sharma, S.K., Lebeda, F.J., Dembek, Z.F., and Mahan, M.A. (2022). Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT\/A) in the Treatment of Peripheral Nerve Injury. Microorganisms, 10.","DOI":"10.3390\/microorganisms10050886"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fncel.2019.00033","article-title":"The success and failure of the Schwann cell response to nerve injury","volume":"13","author":"Jessen","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.expneurol.2006.02.134","article-title":"Local down-regulation of myelin-associated glycoprotein permits axonal sprouting with chronic nerve compression injury","volume":"200","author":"Gupta","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1016\/j.biocel.2006.05.007","article-title":"Schwann cells: Origins and role in axonal maintenance and regeneration","volume":"38","author":"Bhatheja","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.expneurol.2007.06.004","article-title":"A double-transgenic mouse used to track migrating Schwann cells and regenerating axons following engraftment of injured nerves","volume":"207","author":"Hayashi","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1242\/jcs.03168","article-title":"Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage","volume":"119","author":"Triolo","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Marinelli, S., Vacca, V., Ricordy, R., Uggenti, C., Tata, A.M., Luvisetto, S., and Pavone, F. (2012). The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047977"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.3390\/toxins2122890","article-title":"Botulinum neurotoxin for pain management: Insights from animal models","volume":"2","author":"Pavone","year":"2010","journal-title":"Toxins"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1002\/ar.23843","article-title":"Expression of regeneration-associated proteins in primary sensory neurons and regenerating axons after nerve injury\u2014An overview","volume":"301","author":"Joukal","year":"2018","journal-title":"Anat. Rec."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1523\/JNEUROSCI.08-07-02394.1988","article-title":"Nerve growth factors (NGF, BDNF) enhance axonal regeneration but are not required for survival of adult sensory neurons","volume":"8","author":"Lindsay","year":"1988","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1097\/00006534-199806000-00015","article-title":"Nerve injection injury with botulinum toxin","volume":"101","author":"Lu","year":"1998","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.pain.2003.10.008","article-title":"Subcutaneous administration of botulinum toxin A reduces formalin-induced pain","volume":"107","author":"Cui","year":"2004","journal-title":"Pain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14746","DOI":"10.1038\/s41598-017-14997-3","article-title":"Injection of high dose botulinum-toxin A leads to impaired skeletal muscle function and damage of the fibrilar and non-fibrilar structures","volume":"7","author":"Pingel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00018-003-3047-2","article-title":"Role of metallothioneins in peripheral nerve function and regeneration","volume":"60","author":"Ceballos","year":"2003","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2006.12.004","article-title":"Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain","volume":"145","author":"Luvisetto","year":"2007","journal-title":"Neuroscience"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0074-7742(09)87006-2","article-title":"Methods and protocols in peripheral nerve regeneration experimental research: Part III\u2014Electrophysiological evaluation","volume":"87","author":"Navarro","year":"2009","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/00006534-198901000-00024","article-title":"Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat","volume":"83","author":"Bain","year":"1989","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1016\/0303-8467(93)90041-E","article-title":"Nerve growth factor and regeneration of peripheral nervous system","volume":"95","author":"Raivich","year":"1993","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/1479-5876-12-130","article-title":"Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury","volume":"12","author":"Zhang","year":"2014","journal-title":"J. Transl. Med."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/12\/691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:35:16Z","timestamp":1760132116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/12\/691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,8]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["toxins15120691"],"URL":"https:\/\/doi.org\/10.3390\/toxins15120691","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,8]]}}}