Strategies to defeat ketamine-induced neonatal brain injury

• DOI: 10.1016/j.neuroscience.2012.02.015
• Publication Date: 2012-02-23T21:01:13Z
• Authors: C.P. Turner; S. Gutierrez; C. Liu; L. Miller; J. Chou; B. Finucane; A. Carnes; J. Kim; E. Shing; T. Haddad; A. Phillips
• Keywords: Male; Anesthetics, Dissociative; Gene Expression; Apoptosis; Somatosensory Cortex; Microarray Analysis; Immunohistochemistry; Rats; 3. Good health; Rats, Sprague-Dawley; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Animals, Newborn; Brain Injuries; Animals; Female; Ketamine; Neurotoxicity Syndromes

Studies using animal models have shown that general anesthetics such as ketamine trigger widespread and robust apoptosis in the infant rodent brain. Recent clinical evidence suggests that the use of general anesthetics on young children (at ages equivalent to those used in rodent studies) can promote learning deficits as they mature. Thus, there is a growing need to develop strategies to prevent this injury. In this study, we describe a number of independent approaches to address therapeutic intervention. Postnatal day 7 (P7) rats were injected with vehicle (sterile PBS) or the NMDAR antagonist ketamine (20 mg/kg). After 8 h, we prepared brains for immunohistochemical detection of the pro-apoptotic enzyme activated caspase-3 (AC3). Focusing on the somatosensory cortex, AC3-positive cells were then counted in a non-biased stereological manner. We found AC3 levels were markedly increased in ketamine-treated animals. In one study, microarray analysis of the somatosensory cortex from ketamine-treated P7 pups revealed that expression of activity dependent neuroprotective protein (ADNP) was enhanced. Thus, we injected P7 animals with the ADNP peptide fragment NAPVSIPQ (NAP) 15 min before ketamine administration and found we could dose-dependently reverse the injury. In separate studies, pretreatment of P6 animals with 20 mg/kg vitamin D(3) or a nontoxic dose of ketamine (5 mg/kg) also prevented ketamine-induced apoptosis at P7. In contrast, pretreatment of P7 animals with aspirin (30 mg/kg) 15 min before ketamine administration actually increased AC3 counts in some regions. These data show that a number of unique approaches can be taken to address anesthesia-induced neurotoxicity in the infant brain, thus providing MDs with a variety of alternative strategies that enhance therapeutic flexibility.