A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA-induced motor deficit in rats.

Abstract

BACKGROUND AND PURPOSE:

Cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a modified diketopiperazine, is neuroprotective and improves long-term function after hypoxic-ischaemic brain injury in rats. The present studies were designed to examine both the neuroprotective and neurotrophic actions of NNZ-2591 on neurochemical and behavioural changes in a rat model of Parkinson's disease.

EXPERIMENTAL APPROACH:

To examine its protective effect, either NNZ-2591 (20 ng.day(-1)) or saline was given intracerebroventricularly for 3 days starting 2 h after 6-hydroxydopamine (6-OHDA) induced unilateral striatal lesion. In a subsequent experiment either NNZ-2591 (0.2, 1 and 5 mg.day(-1), s.c.) or saline was administered daily for 14 days starting 2 weeks after the lesion. Behavioural and neurochemical outcomes were examined using the adjusting step test and immunohistochemical staining.

KEY RESULTS:

Cyclo-L-glycyl-L-2-allylproline given 2 h after the lesion reduced the degree of motor deficit compared with the saline-treated group. Delayed treatment with NNZ-2591, initiated after the onset of motor deficit, significantly improved motor function from week 7 onwards compared with the saline-treated group. Neither treatment regime altered nigrostriatal dopamine depletion. NNZ-2591 significantly enhanced the expression of doublecortin-positive neuroblasts in the sub-ventricular zone.

CONCLUSIONS AND IMPLICATIONS:

These studies reveal that early treatment with NNZ-2591 protects against the motor deficit induced by 6-OHDA and that treatment initiated after the establishment of motor impairment significantly improves long-term motor function. These effects of NNZ-2591 on functional recovery were independent of dopamine depletion and also appeared not to be symptomatic as the improved motor function was long-lasting. NNZ-2591 has potential as a therapeutic agent for neurodegenerative disorders.

• Authors: R V M Krishnamurthi, S Mathai, A H Kim, R Zhang, J Guan
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 156 Issue 4 Pg. 662-72 (Feb 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19154439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dcx protein, rat
• Diketopiperazines
• Doublecortin Protein
• Neuroprotective Agents
• Peptides, Cyclic
• cyclo-L-glycyl-L-2-allylproline
• Oxidopamine

Topics

• Animals
• Behavior, Animal (drug effects)
• Chromatography, High Pressure Liquid
• Corpus Striatum (drug effects, metabolism)
• Diketopiperazines (pharmacology, therapeutic use)
• Doublecortin Protein
• Immunohistochemistry
• Movement Disorders (etiology, prevention & control)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Oxidopamine
• Parkinsonian Disorders (complications, drug therapy, physiopathology)
• Peptides, Cyclic (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Recovery of Function (drug effects)
• Substantia Nigra (drug effects, metabolism)