Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Abstract

Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-<smlcap>L</smlcap>-carnitine (ALCAR), an acetylated derivative of <smlcap>L</smlcap>-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

“…Neonatal HI is one of major causes of death and long-term neurological impairment in neonates [27, 28]. However, the treatment for HI encephalopathy is limited.…”

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

“…Recent reports demonstrate that administration of ALCAR after injury can improve mitochondrial function [38], decrease swelling in brain after injury [37, 39], and prevent loss of tissue in pediatric injury models [12, 37, 39]. Long term administration of ALCAR improved energy status in healthy mouse brain [107].…”

“…The effects of neonatal HI have been widely studied in the postnatal day 7 rat pup using the Rice-Vannucci method of carotid artery ligation combined with 8% O 2 [37, 39, 138–145]. Our studies using 75 minutes exposure to 8% O 2 result in a moderate injury and evidence of more impairment in male pups compared to females [39, 146, 147]. Our group has determined the neuroprotective effects of ALCAR (100 mg/kg administered by subcutaneous injection) at 0, 4, 24 and 48 hours after HI on postnatal day 7.…”

“…Our group has determined the neuroprotective effects of ALCAR (100 mg/kg administered by subcutaneous injection) at 0, 4, 24 and 48 hours after HI on postnatal day 7. In vivo imaging showed that treatment with ALCAR after HI led to a smaller lesion volume in brain determined at 3, 7 and 28 days after HI [39]. In vivo 1 H-magnetic resonance spectroscopy ( 1 H-MRS) in the same rat pups showed that treatment with ALCAR after HI improved lactate levels and maintained creatine concentration in the ipsilateral hippocampus compared to saline treated pups [37].…”

“…A number clinical trials and case studies have reported efficacy of ALCAR for neuroprotection in conditions leading to central or peripheral nervous system injury in adults [1, 4, 7–22]. Although relatively few studies have determined the efficacy of acetyl-L-carnitine for neuroprotection in models of developmental brain injury, results from these studies are promising [12, 19, 20, 37–39]. …”