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


METHODS
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.


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
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.
Krishnamurthi
R V M
RV
Liggins Institute, University of Auckland, Auckland, New Zealand.
Mathai
S
S
Kim
A H
AH
Zhang
R
R
Guan
J
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D054659:Diketopiperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
C000714848:Dcx protein, rat; D054659:Diketopiperazines; D000089662:Doublecortin Protein; D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; C540261:cyclo-L-glycyl-L-2-allylproline; D016627:Oxidopamine