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Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia–ischemia in adult rats

Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia–ischemia in adult rats
Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia–ischemia in adult rats
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.
diketopiperazine, neuroprotection, central uptake, hypoxia–ischemia, rats
0028-3908
749-762
Guan, J.
c5e8151e-0fa7-4d8e-85bb-8c7ed01a6a60
Mathai, S.
760cd949-20ac-4961-82e0-19f10c51a143
Harris, P.
65908d3a-d64f-436d-829a-fd500923515b
Wen, J. -Y.
8c59f024-8d4e-44ec-9e4c-09257766f248
Zhang, R.
0db08a43-0be0-46fc-bb29-e28a9d0e3243
Brimble, M.
e5285796-9fa1-4bb3-aae4-0f2e7eb5292c
Gluckman, P.
dadc86d4-4eaa-4589-b560-413a9e564558
Guan, J.
c5e8151e-0fa7-4d8e-85bb-8c7ed01a6a60
Mathai, S.
760cd949-20ac-4961-82e0-19f10c51a143
Harris, P.
65908d3a-d64f-436d-829a-fd500923515b
Wen, J. -Y.
8c59f024-8d4e-44ec-9e4c-09257766f248
Zhang, R.
0db08a43-0be0-46fc-bb29-e28a9d0e3243
Brimble, M.
e5285796-9fa1-4bb3-aae4-0f2e7eb5292c
Gluckman, P.
dadc86d4-4eaa-4589-b560-413a9e564558

Guan, J., Mathai, S., Harris, P., Wen, J. -Y., Zhang, R., Brimble, M. and Gluckman, P. (2007) Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia–ischemia in adult rats. Neuropharmacology, 53 (6), 749-762. (doi:10.1016/j.neuropharm.2007.08.010).

Record type: Article

Abstract

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.

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More information

Published date: November 2007
Keywords: diketopiperazine, neuroprotection, central uptake, hypoxia–ischemia, rats

Identifiers

Local EPrints ID: 61184
URI: http://eprints.soton.ac.uk/id/eprint/61184
ISSN: 0028-3908
PURE UUID: 6e35e799-7037-4042-9feb-9a544849dd27

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Date deposited: 09 Oct 2008
Last modified: 15 Mar 2024 11:24

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Contributors

Author: J. Guan
Author: S. Mathai
Author: P. Harris
Author: J. -Y. Wen
Author: R. Zhang
Author: M. Brimble
Author: P. Gluckman

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