On the mechanisms of neuroprotection by creatine and phosphocreatine

• Published in: Journal of neurochemistry 2001-01, Vol.76 (2), p.425-434
• Main Authors: Brustovetsky, Nickolay, Brustovetsky, Tatiana, Dubinsky, Janet M.
• Format: Article
• Language: English
• Subjects: 3-Nitropropionic acid; Animals; Biological and medical sciences; Cells, Cultured; Corpus Striatum - cytology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; creatine; Creatine - administration & dosage; Creatine - pharmacology; Dietary Supplements; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - pharmacology; excitotoxicity; glutamate uptake; Glutamic Acid - toxicity; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Medical sciences; Mitochondria - drug effects; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; Nitro Compounds; Permeability - drug effects; permeability transition; Pharmacology. Drug treatments; phosphocreatine; Phosphocreatine - pharmacology; Propionates - antagonists & inhibitors; Propionates - toxicity; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2001.00052.x

Creatine and phosphocreatine were evaluated for their ability to prevent death of cultured striatal and hippocampal neurons exposed to either glutamate or 3‐nitropropionic acid (3NP) and to inhibit the mitochondrial permeability transition in CNS mitochondria. Phosphocreatine (PCr), and to a lesser extent creatine (Cr), but not (5R,10S)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine hydrogen maleate (MK801), dose‐dependently ameliorated 3NP toxicity when applied simultaneously with the 3NP in Mg2+‐free media. Pre‐treatment of PCr for 2 or 5 days and Cr for 5 days protected against glutamate excitotoxicity equivalent to that achieved by MK801 post‐treatment. The combination of PCr or Cr pre‐treatment and MK801 post‐treatment did not provide additional protection, indicating that both prevented the toxicity attributable to secondary glutamate release. To determine if Cr or PCr directly inhibited the permeability transition, mitochondrial swelling and depolarization were assayed in isolated, purified brain mitochondria. PCr reduced the amount of swelling induced by calcium by 20%. Cr decreased mitochondrial swelling when inhibitors of creatine kinase octamer–dimer transition were present. However, in brain mitochondria prepared from rats fed a diet supplemented with 2% creatine for 2 weeks, the extent of calcium‐induced mitochondrial swelling was not altered. Thus, the neuroprotective properties of PCr and Cr may reflect enhancement of cytoplasmic high‐energy phosphates but not permeability transition inhibition.