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01.10.2012 | Experimental research

Assisted peripheral nerve recovery by KMUP-1, an activator of large-conductance Ca²⁺-activated potassium channel, in a rat model of sciatic nerve crush injury

verfasst von: Chia-Li Chung, Hung-Pei Tsai, Kung-Shing Lee, Kuang-I Chen, Shu-Chuan Wu, Yen-Hsin Kuo, William Winardi, Ing-Chun Chen, Aij-Lie Kwan

Erschienen in: Acta Neurochirurgica | Ausgabe 10/2012

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Abstract

Background

Axonal regeneration in peripheral nerves after injury is a complicated process. Numerous cytokines, growth factors, channels, kinases, and receptors are involved, and matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis subsequent to nerve injury. In this study, the effect of KMUP-1, an activator of large-conductance Ca²⁺-activated potassium channel, on functional recovery, myelinated axon growth, and immunoreactivity of MMP-9 was evaluated in rats subjected to sciatic nerve crush injury.

Method

A total of 144 male Sprague-Dawley rats were divided into the following six groups (n = 24/group): group 1, sham-operated; group 2, sciatic nerve injury without treatment; group 3, injured and vehicle-treated; group 4, injured and treated with 1 mM KMUP-1 by topical application; group 5, injured and treated with 10 mM KMUP-1; group 6, injured and treated with 50 mM KMUP-1. Functional recovery was evaluated using walking track analysis at 1, 2, 3, and 4 weeks (n = 6/group at each time point) after injury. In addition, the number of myelinated axons and MMP-9 in the nerve was also examined.

Findings

Animals subjected to sciatic nerve crush injury had decreased motor function, a reduced number of myelinated axons, and increased MMP-9 in the nerve. Treatment with KMUP-1 concentration-dependently improved functional recovery, increased the number of myelinated axons, and decreased MMP-9.

Conclusions

These results suggest that KMUP-1 may be a novel agent for assisting peripheral nerve recovery after injury. The beneficial effect is probably due to known ability of the compound in activating the nitric oxide/cGMP/protein kinase G pathway.

Britt JM, Kane JR, Spaeth CS, Zuzek A, Robinson GL, Gbanaglo MY, Estler CJ, Boydston EA, Schallert T, Bittner GD (2010) Polyethylene glycol rapidly restores axonal integrity and improves the rate of motor behavior recovery after sciatic nerve crush injury. J Neurophysiol 104:695–703PubMedCrossRef

Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Barrera-Oranday EA, Cabello-García AJ, García-Tamez A, Fernández-Garza NE (2008) Celecoxib accelerates functional recovery after sciatic nerve crush in the rat. J Brachial Plex Peripher Nerve Inj 3:25PubMedCrossRef

Campadelli P, Gangai C, Pasquale F (1999) Automated morphometric analysis in peripheral neuropathies. Comput Biol Med 29:147–156PubMedCrossRef

Chattopadhyay S, Myers RR, Janes J, Shubayev V (2007) Cytokine regulation of MMP-9 in peripheral glia: implications for pathological processes and pain in injured nerve. Brain Behav Immun 21:561–568PubMedCrossRef

Chattopadhyay S, Shubayev VI (2009) MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia 57:1316–1325PubMedCrossRef

Chung H-H, Dai Z-K, Wu B-N, Yeh J-L, Chai C-Y, Chu K-S, Liu C-P, Chen I-J (2010) The xanthine derivative KMUP-1 inhibits models of pulmonary artery hypertension via increased NO and cGMP-dependent inhibition of RhoA/Rho kinase. Br J Pharmacol 160:971–986PubMedCrossRef

Dai Z-K, Cheng Y-J, Chung H-H, Wu J-R, Chen I-J, Wu B-N (2010) KMUP-1 ameliorates monocrotaline-induced pulmonary arterial hypertension through the modulation of Ca²⁺ sensitization and K⁺-channel. Life Sci 86:747–755PubMedCrossRef

George R, Griffin JW (1994) Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp Neurol 129:225–236PubMedCrossRef

Geuna S, Tos P, Guglielmone R, Battiston B, Giacobini-Robecchi MG (2001) Methodological issues in size estimation of myelinated nerve fibers in peripheral nerves. Anat Embryol 204:1–10PubMedCrossRef

10.

Hashikawa-Hobara N, Hashikawa N, Yutani C, Zamami Y, Jin X, Takatori S, Mio M, Kawasaki H (2011) The Akt-nitric oxide-cGMP pathway contributes to nerve growth factor-mediated neurite outgrowth in apolipoprotein E knockout mice. J Pharmacol Exp Ther 338:694–700PubMedCrossRef

11.

Ho PR, Coan GM, Cheng ET, Niell C, Tarn DM, Zhou H, Sierra D, Terris DJ (1998) Repair with collagen tubules linked with brain-derived neurotrophic factor and ciliary neurotrophic factor in a rat sciatic nerve injury model. Arch Otolaryngol Head Neck Surg 124:761–766PubMed

12.

Huebner EA, Strittmatter SM (2009) Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ 48:339–351PubMed

13.

IJkema-Paassen J, Jansen K, Gramsbergen A, Meek MF (2004) Transection of peripheral nerves, bridging strategies and effect evaluation. Biomaterials 25:1583–1592PubMedCrossRef

14.

Kalender AM, Dogan A, Bakan V, Yildiz H, Gokalp MA, Kalender M (2009) Effect of zofenopril on regeneration of sciatic nerve crush injury in a rat model. J Brachial Plex Peripher Nerve Inj 4:6PubMedCrossRef

15.

Li F-Q, Fowler KA, Neil JE, Colton CA, Vitek MP (2010) An apolipoprotein E-mimetic stimulates axonal regeneration and remyelination after peripheral nerve injury. J Pharmacol Exp Thera 334:106–115CrossRef

16.

Lin R-J, Wu B-N, Lo Y-C, Shen K-P, Lin Y-T, Huang C-H, Chen I-J (2002) KMUP-1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo: involvement of cyclic GMP and K⁺ channels. Br J Pharmacol 135:1159–1166PubMedCrossRef

17.

López-vales R, Navarro X, Shimizu T, Baskakis C, Kokotos G, Constantinou-Kokotou V, Stephens D, Dennis EA, David S (2008) Intracellular phospholipase A₂ group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury. Brain 131:2620–2631PubMedCrossRef

18.

Makwana M, Raivich G (2005) Molecular mechanisms in successful peripheral regeneration. FEBS J 272:2628–2638PubMedCrossRef

19.

Shim S, Ming GL (2010) Roles of channels and receptors in the growth cone during PNS axonal regeneration. Exp Neurol 223:38–44PubMedCrossRef

20.

Subbanna PKT, Prasanna CG, Gunale BK, Tyagi MG (2007) Acetyl salicylic acid augments functional recovery following sciatic nerve crush in mice. J Brachial Plex Peripher Nerve Inj 2:3PubMedCrossRef

21.

Varejão ASP, Cabrita AM, Meek MF, Bulas-Cruz J, Filipe VM, Gabriel RC, Ferreira AJ, Geuna S, Winter DA (2003) Ankle kinematics to evaluate functional recovery in crushed rat sciatic nerve. Muscle Nerve 27:706–714PubMedCrossRef

22.

Varejão ASP, Meek MF, Ferreira AJA, Patrício JAB, Cabrita AMS (2001) Functional evaluation of peripheral nerve regeneration in the rat: walking track analysis. J Neurosci Meth 108:1–9CrossRef

23.

Wu B-N, Lin R-J, Lin C-Y, Shen K-P, Chiang L-C, Chen I-J (2001) A xanthine-based KMUP-1 with cyclic GMP enhancing and K⁺ channels opening activities in rat aortic smooth muscle. Br J Pharmacol 134:265–274PubMedCrossRef

24.

Wu B-N, Lin R-J, Lo Y-C, Shen K-P, Wang C-C, Lin Y-T, Chen I-J (2004) KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K⁺ channels. Br J Pharmacol 142:1105–1114PubMedCrossRef

25.

Wu B-N, Tu H-F, Welsh DG, Chen I-J (2005) KMUP-1 activates BK_Ca channels in basilar artery myocytes via cyclic nucleotide-dependent protein kinases. Br J Pharmacol 146:862–871PubMedCrossRef

26.

Yeh J-L, Hsu J-H, Wu P-J, Liou S-F, Liu C-P, Chen I-J, Wu B-N, Dai Z-K, Wu J-R (2010) KMUP-1 attenuates isoprenaline-induced cardiac hypertrophy in rats through NO/cGMP/PKG and ERK1/2/calcineurin A pathways. Br J Pharmacol 159:1151–1160PubMedCrossRef

27.

Zhang H, Chang M, Hansen CN, Basso DM, Noble-Haeusslein LJ (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8:206–220PubMedCrossRef

28.

Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675–2680PubMedCrossRef

Titel: Assisted peripheral nerve recovery by KMUP-1, an activator of large-conductance Ca2+-activated potassium channel, in a rat model of sciatic nerve crush injury
verfasst von: Chia-Li Chung
Hung-Pei Tsai
Kung-Shing Lee
Kuang-I Chen
Shu-Chuan Wu
Yen-Hsin Kuo
William Winardi
Ing-Chun Chen
Aij-Lie Kwan
Publikationsdatum: 01.10.2012
Verlag: Springer Vienna
Erschienen in: Acta Neurochirurgica / Ausgabe 10/2012
Print ISSN: 0001-6268
Elektronische ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-012-1433-y

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Abstract

Background

Method

Findings

Conclusions

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