Changes in Cellular Bioenergetic State Following Graded Traumatic Brain Injury in Rats: Determination by Phosphorus 31 Magnetic Resonance Spectroscopy

Abstract

Phosphorus 31 magnetic resonance spectroscopy (31P MRS) was used to study noninvasively the intracellular free Mg2+ concentration and cellular bioenergetic state of rat brain in vivo before and after fluid percussion-induced traumatic brain injury of graded severity. Brain injury was induced at four levels: low (1.0 +/- 0.5 atm); moderate (2.1 +/- 0.4 atm); high (3.9 +/- 0.9 atm); and severe (5.9 +/- 0.7 atm). Prior to injury, mean intracellular values for all groups (n = 24; mean +/- SE) were as follows: pH = 7.11 +/- 0.03; free [Mg2+] = 0.99 +/- 0.07 mM; cytosolic [ADP] = 25.2 +/- 0.8 nmol/g wet weight; cytosolic [AMP] = 0.29 +/- 0.02 nmol/g wet weight; cytosolic phosphorylation potential = 118.5 +/- 3.1 X 10(3) M-1; free energy of ATP hydrolysis = 62.11 +/- 0.04 kJ/mole; and energy charge = 0.99 +/- 0.01. Following every level of injury, there were decreases in intracellular free Mg2+ concentration, and alterations in the intracellular pH. These posttraumatic changes in Mg2+ and pH induced shifts in the equilibrium constants of the creatine kinase, adenylate kinase, and ATPase reactions, resulting in alterations in [ADP], [AMP], cytosolic phosphorylation potential, and free energy of hydrolysis, but not in the energy charge. The alterations in cytosolic phosphorylation potential following trauma were linearly correlated with the changes in intracellular free Mg2+ concentration. None of the individual bioenergetic parameters could be correlated with the severity of injury over the entire injury range; however, an association between cytosolic phosphorylation potential and reversibility of injury was apparent. These results suggest that reductions in cellular bioenergetic state following traumatic brain injury occur through a posttraumatic decrease in the cells' capacity for oxidative phosphorylation, which itself may be directly related to the intracellular free Mg2+ concentration.

Metabolic, Neurochemical, and Histologic Responses to Vibrissa Motor Cortex Stimulation after Traumatic Brain Injury

“…The mechanisms responsible for this injury-induced vulnerability are multifactorial. However, those most relevant to the current study include an uncoupling between blood flow and metabolism (Ginsberg et al, 1997;Jiang et al, 2000) and a reduction in oxidative metabolism Jiang et al, 1999Jiang et al, , 2000Vink et al, 1988), both of which may contribute to the reported reduction in ATP (Lee et al, 1999). Given that these factors suggest the brain is in a state of energy crisis after TBI, it is not surprising that an added energy demand induced by direct cortical activation can, as demonstrated in the current study, result in additional cell loss.…”

Structural and Functional Damage Sustained by Mitochondria after Traumatic Brain Injury in the Rat: Evidence for Differentially Sensitive Populations in the Cortex and Hippocampus

“…In fact, apoptosis can selectively eliminate mitochondria in the presence of caspase inhibitors (Xue et al, 2001), and oxidative stress has been shown to reduce mitochondrial protein yield from the liver in a model of chronic ethanol consumption (Cahill et al, 1997). Damage or elimination of mitochondrial populations after injury may underlie the sustained hypometabolic state reported to be initiated within hours after experimental TBI (Vink et al, 1988;Yoshino et al, 1991;Ginsberg et al, 1997;Moore et al, 2000) that is coupled to increased brain lactate concentration (Nilsson et al, 1990;Kawamata et al, 1995) and reduced cerebral blood flow (Yamakami and McIntosh, 1991;Ginsberg et al, 1997), suggesting that cerebral metabolism may shift towards anaerobic glycolysis. The acute decrease in the [ATP]/[ADP][P i ] ratio that arises from increases in cytosolic ADP (Vink et al, 1988;Headrick et al, 1994) and reductions in tissue ATP concentrations (Signoretti et al, 2001) (Table 1) incorporates both a loss of energy production and an increase in energy demand after moderate, but not mild (Yang et al, 1985), brain injury.…”

“…Damage or elimination of mitochondrial populations after injury may underlie the sustained hypometabolic state reported to be initiated within hours after experimental TBI (Vink et al, 1988;Yoshino et al, 1991;Ginsberg et al, 1997;Moore et al, 2000) that is coupled to increased brain lactate concentration (Nilsson et al, 1990;Kawamata et al, 1995) and reduced cerebral blood flow (Yamakami and McIntosh, 1991;Ginsberg et al, 1997), suggesting that cerebral metabolism may shift towards anaerobic glycolysis. The acute decrease in the [ATP]/[ADP][P i ] ratio that arises from increases in cytosolic ADP (Vink et al, 1988;Headrick et al, 1994) and reductions in tissue ATP concentrations (Signoretti et al, 2001) (Table 1) incorporates both a loss of energy production and an increase in energy demand after moderate, but not mild (Yang et al, 1985), brain injury. Cerebral metabolic alterations and mitochondrial damage may contribute to the progressive cell death observed in the parietotemporal cortex and CA3 region of the hippocampus after FP brain injury (Hicks et al, 1996;Smith et al, 1997) that would be accompanied by additional loss of mitochondria.…”

Cerebral Blood Flow and Autoregulation After Pediatric Traumatic Brain Injury

“…However, decrease in CBF may not be problematic if, following TBI, baseline CMRO 2 is low and there is a compensatory increase in oxygen extraction fraction [70]. Regional alterations of brain metabolism, reduction in metabolic rates and energy crisis have been demonstrated in adult patients after TBI [71][72][73]. Although the incidence of cerebral ischemia was reported to be low (1% when using oxygen extraction fraction and cerebral venous oxygen content, and 2.4% when using microdialysis technique), the incidence of metabolic crisis (elevated lactate/pyruvate ratio) following TBI was high (25%) [74].…”