Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy

Fei Li, Viktor R. Drel, Csaba Szabo, Martin J. Stevens, Irina G. Obrosova

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects. This study evaluated potential synergistic interactions between low doses of the potent and specific PARP inhibitor 1,5-isoquinolinediol (ISO) and one of two vasodilators, the ACE inhibitor lisinopril (LIS) and the β2-adrenoceptor agonist salbutamol (SAL) in the model of early PDN. Control and streptozotocin (STZ)-induced diabetic rats were treated with either ISO pins LIS or ISO plus SAL for 2 weeks after an initial 2 weeks without treatment. ISO (intraperitoneally) and LIS and SAL (both in the drinking water) were used in subtherapeutic doses, resulting in a minor correction of diabetes-associated sciatic motor and hind-limb digital sensory nerve conduction deficits when administered as monotherapies. Both combination treatments corrected endoneurial blood flow and vascular conductance deficits in STZ-induced diabetic rats. ISO plus SAL corrected all other changes of PDN, i.e., motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) deficits as well as thermal and mechanical hyperalgesia. With ISO plus LIS, no significant correction of MNCV was observed, and the effect on thermal hyperalgesia was quite modest. SNCV and mechanical hyperalgesia were corrected. In vitro studies in human endothelial and Schwann cells showed early accumulation of poly(ADP-rilbosyl)ated proteins (Western blot analysis) in response to high glucose, thus suggesting the importance of PARP activation in human PDN. In conclusion, low-dose PARP inhibitor-containing combination therapies may constitute a new approach for treatment of PDN.

Original languageEnglish (US)
Pages (from-to)1514-1522
Number of pages9
JournalDiabetes
Volume54
Issue number5
DOIs
StatePublished - May 2005
Externally publishedYes

Fingerprint

Diabetic Neuropathies
Neural Conduction
Lisinopril
Peripheral Nervous System Diseases
Albuterol
Hyperalgesia
Poly(ADP-ribose) Polymerases
Streptozocin
Premature Aging
Therapeutics
Genomic Instability
Schwann Cells
Vasodilator Agents
Angiotensin-Converting Enzyme Inhibitors
DNA Repair
Drinking Water
Adenosine Diphosphate
Adrenergic Receptors
Blood Vessels
Extremities

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. / Li, Fei; Drel, Viktor R.; Szabo, Csaba; Stevens, Martin J.; Obrosova, Irina G.

In: Diabetes, Vol. 54, No. 5, 05.2005, p. 1514-1522.

Research output: Contribution to journalArticle

Li, Fei ; Drel, Viktor R. ; Szabo, Csaba ; Stevens, Martin J. ; Obrosova, Irina G. / Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. In: Diabetes. 2005 ; Vol. 54, No. 5. pp. 1514-1522.
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