Introduction
A considerable number of neuropeptides have been shown to be neuroprotective tested in various animal models with ischemic brain injuries. However the central delivery of peptide has always been problematic due to their large molecular weight and potential mitogenic effect after being administered into the peripheral circulation. Diketopiperazine (DKP)s are a group of cyclic forms of bipeptides, naturally occurring in the central nervous system. The current experiment examined the neuroprotective effects of a native DKP and its analogues, modified to improve its potency on neuroprotection.
Methods
An analogue of DKP was modified to improve the potency of neuroprotection. The effects of neuronal survival of both a native DKP and its analogue following glutamate + 3NP neurotoxicity were first examined in cerebellar neuronal culture. The neuroprotection of the native DKP and its analogue were also tested in adult rats with hypoxic-ischemic brain injury.
Results
Both the native DKP and its analogue prevented cereballar neuronal death from glutamate/3-NP induced neurotoxicity in a dose dependent manner. The effect of the analogue on neuronal survival was more potent (10 pM-1 nM) compared to that of native DKP (1–100 nM). Central administration of either native DKP (200 ng/rat, icv) or its analogue (2–20 ng/rat, icv) reduced neuronal loss in the lateral cortex, hippocampus and striatum, also in a dose dependent manner. Peripheral administration of the analogue significantly improved neuronal outcome 7 days after HI injury, however the degree of neuroprotection was not as strong compared to that after central administration.
Discussion
Current study demonstrated for the first time that the cyclic form of proline containing bipeptides were neuroprotective. The data suggest a potential pharmaceutical development for treating ischemic brain injury.