Neuroprotection of Creatine Supplementation in Neonatal Rats with Transient Cerebral Hypoxia-Ischemia

Abstract

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°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 β-nucleotide triphosphate (PCr/βNTP) 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.

Creatine and guanidinoacetate transport at blood‐brain and blood‐cerebrospinal fluid barriers

“…Indeed, Cr administration can exert protective effects in various neurodegenerative processes, including Huntington's and Parkinson's diseases Bender et al 2006;Hersch et al 2006;Klein and Ferrante 2007). Creatine was also demonstrated to exert neuroprotective effects, both in vitro and in vivo, against anoxic and ischemic damage (Balestrino et al 2002;Adcock et al 2002;Lensman et al 2006) as well as against traumatic brain injury (Sullivan et al 2000) and spinal cord injury (Hausmann et al 2002).…”

Structural correlates of the creatine transporter function regulation: the undiscovered country

“…The potential for therapeutic creatine augmentation in the setting of cardiac myopathies was demonstrated in mouse model of myocardial infraction (Lygate et al 2012) and it has recently been reviewed elsewhere (Zervou et al 2015). Cr supplementation has been reported to have a protective effect in neurons, myoblasts, and cardiomyocytes in culture when the cells are subjected to hypoxic and increased oxidative stressors (Adcock et al 1999(Adcock et al , 2002Balestrino et al 2002;Caretti et al 2010;Santacruz et al 2015a;Sartini et al 2012). Similar positive results have been reported in studies of the effects of Cr supplementation in animal models of neonatal hypoxia (Allah Yar et al 2015;Ellery et al 2013), and in a study with human volunteers that evaluated the Fig.…”

Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy

“…Other groups have studied the neuroprotective effects of Cr, an essential component of the creatine kinase/PCr energy shuttle that provides immediate replenishment of ATP. Indeed, the supplementation of Cr for 3 days prior to a hypoxic-ischemic insult in immature rats increased the PCr/β-NTP and PCr/Pi ratios and reduced cerebral edema, as measured by MRS and diffusion-weighted imaging [43] . Despite the lactacidosis during and immediately after HI, there is a rapid rise in intracellular pH of the brain during reperfusion [7] .…”