Pre-injury magnesium treatment prevents traumatic brain injury-induced hippocampal ERK activation, neuronal loss, and cognitive dysfunction in the radial-arm maze test

We studied the effect of pre-injury magnesium (Mg²⁺) treatment on hippocampal extracellular signal-regulated kinase (ERK) activation induced by lateral fluid-percussion (FP) brain injury, and on working and reference memory in the radial-arm maze test in rats subjected to such traumatic brain injury (TBI) (n = 56) or to sham injury (n = 12). In the ipsilateral hippocampus, an increase in the phospho-ERK level was detected at 10 min after injury in rats subjected to FP brain injury of moderate severity (1.9-2.0 atm) as compared to sham-injured controls (p < 0.01), and was maintained for at least 120 min after injury (p < 0.05). In the contralateral hippocampus, the phospho-ERK level was transiently increased at 10 min after injury but fell to nearly its basal level by 30 min. When MgCl₂ solution (150 μmol) was infused intravenously from 20 min to 5 min before injury (n = 4-5), brain injury-induced ERK activation was significantly inhibited in the ipsilateral hippocampus at 60 min but not at 10 min after injury. Mg²⁺ treatment also significantly prevented injury-induced neuronal loss in the ipsilateral hippocampus (p < 0.05 vs. vehicle-treated, brain-injured controls). At 2 weeks after injury, Mg²⁺ treatment was found to have significantly prevented injury-induced impairments in working (p < 0.0001 vs. vehicle-treated, brain-injured controls) and reference memory (p < 0.05) in the radial-arm maze test. The present study demonstrates that pretreatment with Mg²⁺ prevents post-traumatic hippocampal ERK activation and neuronal loss, and cognitive dysfunction in the radial-arm maze test.