Changes of mGluR4 and the effects of its specific agonist L-AP4 in a rodent model of diffuse brain injury.

OBJECTIVE: Excessive release of glutamate from nerve terminals following diffuse brain injury (DBI) is thought to contribute to neuronal calcium overload leading to calcium-mediated cell damage. Metabotropic glutamate receptor subtype 4 (mGluR4) is regarded as one of the neuroprotective receptors in mammalian brains. Therefore, the mGluR4 specific agonists might exert neuroprotective effects after DBI. The focus of this study is to examine the changes of expression of mGluR4 after DBI and the role of its specific agonist L-AP4 in vivo.

METHODS: One hundred and sixty-one male SD rats were randomized into two groups. Group A included normal control, sham-operated control and DBI group. DBI was produced by Marmarou's diffuse head injury model. The mRNA expression of mGluR4 was detected by hybridization in situ. Group B included DBI alone, DBI treated with normal saline and DBI treated with L-AP4. All DBI rats were trained in a series of performance tests, following which they were subjected to DBI. At 1 and 12 h, animals were injected intracerebroventricularly with L-AP4 (100 mM, 10 microl) or normal saline, respectively. The rats were tested for motor and cognitive performance at 1, 3, 7, 14 days post-injury and the damaged neurons were detected.

RESULTS: There was no significant difference between the normal control group and sham-operated group in the expression of mGluR4 (P>0.05). The animals exposed to DBI showed a significant increased expression of mRNA of mGluR4 compared with that of the sham-operated animals 1 h after injuries (P<0.05). At 6 h, the evolution of neuronal expression of mGluR4 in the trauma alone group was relatively static. Compared with saline-treated control animals, rats treated with L-AP4 showed decreased number of damaged neurons and a better motor and cognitive performance.

CONCLUSIONS: The increased expression of mGluR4 is an important process in the pathophysiological of DBI and its specific agonist L-AP4 can provide a remarkable neuroprotection against DBI not only at the histopathological level but also in the motor and cognitive performance.