Creatine Increases Survival and Suppresses Seizures in the Hypoxic Immature Rat

Abstract

The incidence of clinical seizures is highest in the newborn period. At this developmental stage seizures have many causes, with hypoxia and ischemia thought to be the most common. In rat pups hypoxia produces seizures most frequently at 10-12 d of age. Brain cellular energy metabolism increases between 5 and 25 d of age in the rat, as indicated in vivo by the phosphocreatine (PCr)/nucleoside triphosphate (NTP) ratio measured by 31P nuclear magnetic resonance (NMR) spectroscopy. Brain PCr/NTP ratios are approximately the same in 10-12-d-old rats and human term newborns, the ages of high seizure susceptibility. Thus, low Cr or PCr may be important in susceptibility to hypoxic seizures in the metabolically immature brain. To test this hypothesis, rat pups were injected with Cr for 3 d before exposing them to hypoxia on postnatal d 10 or 20. Before and during hypoxia, the electrocortical activity or 31P nuclear magnetic resonance spectra were measured. At 10 but not 20 d, Cr injections increased brain PCr/NTP ratios, decreased hypoxia-induced seizures and deaths, and enhanced brain PCr and ATP recoveries after hypoxia. Thus, Cr protects the metabolically immature brain from hypoxia-induced seizures and, perhaps, from cellular injury. These results may be directly relevant to the human newborn.

Proton Magnetic Resonance Spectroscopy Reveals Medial Temporal Metabolic Abnormalities in Adolescents With History of Preterm Birth

“…It has been suggested that low Cr concentrations in an immature brain may increase susceptibility to brain damage (i.e., because of hypoxic episodes) (23). Cr depletion reported in this investigation agreed with other studies that demonstrated depletion of Cr in schizophrenic patients with hippocampal reductions (24) and in degenerative brain lesions (25).…”

Protective effects of oral creatine supplementation on spinal cord injury in rats

“…Several reports have shown positive e ects of creatine and its analogs on neuronal survival in culture following stress with glutamate or betaamyloid, 18 as well as in vivo in the brains of newborn mammals under conditions of anoxia. 20,25,36 In transgenic mice models of ALS 22 and Huntington's disease 23 creatine was shown to increase life span and improve motor behavior. Indeed, the recent study by Sullivan and coworkers shows that creatine brings about a signi®cant neuroprotection in traumatic brain injury by decreasing the extent of cortical damage by as much as 50% in rats.…”

“…18 ± 21 In animal models of several neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) 22 and Huntington's disease, 23 creatine has proven to be a remarkably potent neuroprotective agent. Orally supplemented creatine is transported by a speci®c creatine transporter into muscle and neural tissues 24 as measured non-invasively by 31 P-NMP spectroscopy, giving rise to a signi®cantly increased PCr/ATP ratio in the rat brain 25 or by 1H-NMR spectroscopy in either creatine-de®cient patients 26 or healthy subjects, 27 showing that total creatine concentration is elevated in the brain after creatine supplementation. In a recent study with several animal species the elevation by creatine supplementation of total creatine into various organs including the brain has been con®rmed by chemical analysis.…”

Brain Creatine Kinase and Creatine Transporter Proteins in Normal and Creatine-Treated Rabbit Pups

“…Hypoxia causes seizures in rat and rabbit pups at ages when brain PCr/NTP ratio has increased about 50% [15,17]. These hypoxia-induced seizures are blocked by Cr with an associated increase in PCr/NTP ratio in both species.…”