Calpain Inhibitor AK295 Attenuates Motor and Cognitive Deficits Following Experimental Brain Injury in the Rat

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 8; pp. 3428 - 3433
• Main Authors: Saatman, Kathryn E., Murai, Hisayuki, Bartus, Raymond T., Smith, Douglas H., Hayward, Neil J., Perri, Brian R., McIntosh, Tracy K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 16.04.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Biochemistry; Blood flow; Brain injuries; Brain Injuries - drug therapy; Brain Injuries - etiology; Brain Injuries - physiopathology; Calcium; Calpain - antagonists & inhibitors; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cysteine Proteinase Inhibitors - administration & dosage; Cysteine Proteinase Inhibitors - pharmacology; Dipeptides - administration & dosage; Dipeptides - pharmacology; Disease Models, Animal; Head injuries; Male; Mazes; Memory; Memory - drug effects; Motor ability; Neurology; Physical trauma; Psychomotor Performance - drug effects; Rats; Rats, Sprague-Dawley; Rodents; Traumatic brain injury; Vehicles; Weight loss
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.8.3428

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.