Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

F. Li, Csaba Szabo, P. Pacher, G. J. Southan, O. I. Abatan, T. Charniauskaya, M. J. Stevens, I. G. Obrosova

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Aims/hypothesis. Poly(ADP-ribose) polymerase activation depletes NAD + and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg·kg-1·day-1) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and high-energy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry. Results. Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADP-ribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both). In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD+:NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats. Conclusions/interpretation. Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.

Original languageEnglish (US)
Pages (from-to)710-717
Number of pages8
JournalDiabetologia
Volume47
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Fingerprint

Peripheral Nervous System Diseases
Streptozocin
Neural Conduction
NAD
Poly Adenosine Diphosphate Ribose
Phosphocreatine
Diabetic Neuropathies
Sciatic Nerve
Phosphates
Therapeutics
Poly(ADP-ribose) Polymerases
Sorbitol
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Poly(ADP-ribose) Polymerase Inhibitors
Creatine
Schwann Cells
Fructose
L-Lactate Dehydrogenase
Protein Kinase C
Blood Vessels

Keywords

  • Energy state
  • Motor and sensory nerve conduction
  • Nerve blood flow
  • Oxidative and nitrosative stress
  • Peripheral diabetic neuropathy
  • PJ34
  • Poly(ADP-ribose) polymerase
  • Rat
  • Sorbitol pathway of glucose metabolism
  • Streptozotocin-diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy. / Li, F.; Szabo, Csaba; Pacher, P.; Southan, G. J.; Abatan, O. I.; Charniauskaya, T.; Stevens, M. J.; Obrosova, I. G.

In: Diabetologia, Vol. 47, No. 4, 04.2004, p. 710-717.

Research output: Contribution to journalArticle

Li, F. ; Szabo, Csaba ; Pacher, P. ; Southan, G. J. ; Abatan, O. I. ; Charniauskaya, T. ; Stevens, M. J. ; Obrosova, I. G. / Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy. In: Diabetologia. 2004 ; Vol. 47, No. 4. pp. 710-717.
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AU - Pacher, P.

AU - Southan, G. J.

AU - Abatan, O. I.

AU - Charniauskaya, T.

AU - Stevens, M. J.

AU - Obrosova, I. G.

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N2 - Aims/hypothesis. Poly(ADP-ribose) polymerase activation depletes NAD + and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg·kg-1·day-1) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and high-energy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry. Results. Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADP-ribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both). In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD+:NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats. Conclusions/interpretation. Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.

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KW - Rat

KW - Sorbitol pathway of glucose metabolism

KW - Streptozotocin-diabetes

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