Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice

  • Authors:
    • Viktor R. Drel
    • Pal Pacher
    • Roman Stavniichuk
    • Weizheng Xu
    • Jie Zhang
    • Tamara M. Kuchmerovska
    • Barbara Slusher
    • Irina G. Obrosova
  • View Affiliations

  • Published online on: May 23, 2011     https://doi.org/10.3892/ijmm.2011.709
  • Pages: 629-635
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Abstract

Poly(ADP-ribose) polymerase (PARP) activation has been implicated in the pathogenesis of diabetic complications, including nephropathy and peripheral neuropathy. This study aimed at evaluating the manifestations of both complications in diabetic Akita mice, a model of Type 1 (insulin-dependent) diabetes, and their amenability to treatment with the potent PARP inhibitor, 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427). Male non-diabetic C57Bl6/J and diabetic C57Bl/6-Ins2Akita/J (Akita) mice were maintained with or without treatment with GPI-15427, 30 mg/kg/day, for 4 weeks starting from 16 weeks of age. Sixteen week-old Akita mice displayed sensory nerve conduction velocity (SNCV) deficit, whereas the motor nerve conduction velocity (MNCV) tended to decrease, but the difference with controls did not achieve statistical significance. They also developed thermal and mechanical hypoalgesia and tactile allodynia. SNCV deficit, mechanical hypoalgesia, and tactile allodynia progressed with age whereas the severity of thermal hypoalgesia was similar in 16- and 20-week-old Akita mice. PARP inhibition alleviated, although it did not completely reverse, SNCV deficit, thermal and mechanical hypoalgesia and tactile allodynia. Sixteen-week-old Akita mice displayed MNCV deficit (41.3±2.5 vs. 51.0±1.2 m/sec in non-diabetic controls, P<0.01), axonal atrophy of myelinated fibers, kidney hypertrophy, and albuminuria. MNCV slowing, axonal atrophy, and kidney hypertrophy, but not albuminuria, were less severe in GPI-15427-treated age-matched Akita mice. Neuroprotective and nephroprotective effects of PARP inhibition were not due to alleviation of diabetic hyperglycemia, or peripheral nerve p38 mitogen-activated protein kinase activation. GPI-15427 did not affect any variables in control mice. In conclusion, the findings support an important role for PARP activation in diabetic peripheral neuropathy and kidney hypertrophy associated with Type 1 diabetes, and provide rationale for development and further studies of PARP inhibitors, for the prevention and treatment of these complications.

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October 2011
Volume 28 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Drel VR, Pacher P, Stavniichuk R, Xu W, Zhang J, Kuchmerovska TM, Slusher B and Obrosova IG: Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. Int J Mol Med 28: 629-635, 2011.
APA
Drel, V.R., Pacher, P., Stavniichuk, R., Xu, W., Zhang, J., Kuchmerovska, T.M. ... Obrosova, I.G. (2011). Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. International Journal of Molecular Medicine, 28, 629-635. https://doi.org/10.3892/ijmm.2011.709
MLA
Drel, V. R., Pacher, P., Stavniichuk, R., Xu, W., Zhang, J., Kuchmerovska, T. M., Slusher, B., Obrosova, I. G."Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice". International Journal of Molecular Medicine 28.4 (2011): 629-635.
Chicago
Drel, V. R., Pacher, P., Stavniichuk, R., Xu, W., Zhang, J., Kuchmerovska, T. M., Slusher, B., Obrosova, I. G."Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice". International Journal of Molecular Medicine 28, no. 4 (2011): 629-635. https://doi.org/10.3892/ijmm.2011.709