Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat

Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain, In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)(3)-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats, Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n = 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (II = 10), Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury, At 18 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P < 0.005), At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P < 0.01), However, brain-injured, AK295-treated animals showed markedly improved motor scores (P < 0.02), which were not significantly different from sham (uninjured) animals, Vehicle-treated, Injured animals demonstrated a profound cognitive deficit (P < 0.001), which was significantly attenuated by AK295 treatment (P < 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction.