title: Best time window for the use of calcium-modulating agents to improve functional recovery in injured peripheral nerves-An experiment in rats.
abstract: Peripheral nerve injury can have a devastating effect on daily life. Calcium concentrations in nerve fibers drastically increase after nerve injury, and this activates downstream processes leading to neuron death. Our previous studies showed that calcium-modulating agents decrease calcium accumulation, which aids in regeneration of injured peripheral nerves; however, the optimal therapeutic window for this application has not yet been identified. In this study, we show that calcium clearance after nerve injury is positively correlated with functional recovery in rats suffering from a crushed sciatic nerve injury. After the nerve injury, calcium accumulation increased. Peak volume is from 2 to 8 weeks post injury; calcium accumulation then gradually decreased over the following 24-week period. The compound muscle action potential (CMAP) measurement from the extensor digitorum longus muscle recovered to nearly normal levels in 24 weeks. Simultaneously, real-time polymerase chain reaction results showed that upregulation of calcium-ATPase (a membrane protein that transports calcium out of nerve fibers) mRNA peaked at 12 weeks. These results suggest that without intervention, the peak in calcium-ATPase mRNA expression in the injured nerve occurs after the peak in calcium accumulation, and CMAP recovery continues beyond 24 weeks. Immediately using calcium-modulating agents after crushed nerve injury improved functional recovery. These studies suggest that a crucial time frame in which to initiate effective clinical approaches to accelerate calcium clearance and nerve regeneration would be prior to 2 weeks post injury. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Froedtert Health-Community Memorial Hospital, Medical College of Wisconsin, Milwaukee.
authors.forename: Feng-Yi
authors.initials: FY
authors.lastname: Shen
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Michael
authors.initials: M
authors.lastname: Agresti
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Lin-Ling
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Hani S
authors.initials: HS
authors.lastname: Matloub
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: John A
authors.initials: JA
authors.lastname: LoGiudice
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Robert
authors.initials: R
authors.lastname: Havlik
authors.affiliation: Department of Hand Surgery, Huashan Hospital, Fudan University and Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hand Surgery, Huashan Hospital, Fudan University and Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China.
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Gu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee.
authors.forename: Ji-Geng
authors.initials: JG
authors.lastname: Yan
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D008297:Male; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D002116:Calcitonin; D009543:Nifedipine; D002118:Calcium
keywords: calcium influx; calcium modulating; calcium-ATPase; nerve injury; nerve regeneration