| Autor: |
Guan J; The Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. j.guan@auckland.ac.nz, Mathai S, Harris P, Wen JY, Zhang R, Brimble M, Gluckman P |
| Jazyk: |
angličtina |
| Zdroj: |
Neuropharmacology [Neuropharmacology] 2007 Nov; Vol. 53 (6), pp. 749-62. Date of Electronic Publication: 2007 Aug 19. |
| DOI: |
10.1016/j.neuropharm.2007.08.010 |
| Abstrakt: |
The current study describes the neuroprotective effects of an endogenous diketopiperazine, cyclo-glycyl-proline (cyclic GP), in rats with hypoxic-ischemic brain injury and the pre-clinical development of an analogue, cyclo-L-glycyl-L-2-allylproline (NNZ 2591), modified for improved bioavailability. The compounds were given either intracerebroventricularly or subcutaneously 2h after hypoxia-ischemia. Histology, immunohistochemistry and behavior were used to evaluate treatment effects. The central uptake of NNZ 2591 was also examined in normal and hypoxic-ischemic injured rats by HPLC-mass spectrometry. Central administration of cyclic GP or NNZ 2591 reduced the extent of brain damage in the lateral cortex, the hippocampus and the striatum (p<0.001), with NNZ 2591 being more potent. NNZ 2591 was stable in the plasma and crossed the blood-brain barrier independent of hypoxic-ischemic injury. The level of NNZ 2591 in the CSF was maintained for 2 h after a single subcutaneous dose, and modest neuroprotection was seen after a bolus subcutaneous administration (overall p<0.001). Treatment with NNZ 2591 for 5 d subcutaneously improved somatosensory-motor function (p<0.05) and long-term histological outcome (overall p<0.0001). NNZ 2591 treatment not only reduced both caspase-3 mediated apoptosis and microglial activation but also enhanced astrocytic reactivity, which may mediate its protective effect. The pharmacokinetic profile and potent long-term protective effects of NNZ 2591 suggests its utility for the treatment of ischemic brain injury and other neurological conditions requiring chronic intervention. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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