Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia.
We hypothesized that creatine (Cr) supplementation would preserve energy metabolism and thus ameliorate the energy failure and the extent of brain edema seen after severe but transient cerebral hypoxia-ischemia (HI) in the neonatal rat model. Six-day-old (P6) rats received subcutaneous Cr monohydrate injections for 3 consecutive days (3 g/kg body weight/day), followed by 31P-magnetic resonance spectroscopy (MRS) at P9. In a second group, P4 rats received the same Cr dose as above for 3 days prior to unilateral common carotid artery ligation followed 1 h later by 100 min of hypoxia (8% O2) at P7. Rats were maintained at 37 degrees C rectal temperature until magnetic resonance imaging was performed 24 h after HI. Cr supplementation for 3 days significantly increased the energy potential, i.e. the ratio of phosphocreatine to beta-nucleotide triphosphate (PCr/betaNTP) and PCr/inorganic phosphate (PCr/Pi) as measured by 31P-MRS. Rats with hemispheric cerebral hypoxic-ischemic insult that had received Cr showed a significant reduction (25%) of the volume of edemic brain tissue compared with controls as calculated from diffusion-weighted images (DWI). Thus, prophylactic Cr supplementation demonstrated a significant neuroprotective effect 24 h after transient cerebral HI. We hypothesize that neuroprotection is probably due to the availability of a larger metabolic substrate pool leading to a reduction of the secondary energy failure because DWI has been reported to correlate with the PCr/Pi ratio in the acute phase of injury. Additional protection by Cr may be related to prevention of calcium overload, prevention of mitochondrial permeability transition pore opening and direct antioxidant effects.
Adcock
Kathryn H
KH
Neuroradiology and Magnetic Resonance Research, University Children's Hospital, Zurich, Switzerland.
Nedelcu
Johann
J
Loenneker
Thomas
T
Martin
Ernst
E
Wallimann
Theo
T
Wagner
Bendicht P
BP
D000818:Animals; D000831:Animals, Newborn; D001929:Brain Edema / Q000188:drug therapy; D003401:Creatine / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013687:Telencephalon / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
D018696:Neuroprotective Agents; D003401:Creatine