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 (n = 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 48 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.
Saatman
K E
KE
Division of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA.
Murai
H
H
Bartus
R T
RT
Smith
D H
DH
Hayward
N J
NJ
Perri
B R
BR
McIntosh
T K
TK
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D008568:Memory / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C090138:AK 295; D002154:Calpain