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A novel diketopiperazine improves functional recovery given after the onset of 6‐OHDA‐induced motor deficit in rats
Author(s) -
Krishnamurthi RVM,
Mathai S,
Kim AH,
Zhang R,
Guan J
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00064.x
Subject(s) - chemistry , neuroprotection , neurochemical , lesion , medicine , dopamine , neuroscience , endocrinology , psychology , pathology
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. Mandarin translation of abstract