Glucose metabolism and acidosis in the metabolic penumbra of rat brain

Abstract

The characterization of tissue acid-base status related to the penumbral zone of increased glucose consumption surrounding a focal cerebral ischemic lesion may suggest therapeutic techniques to maximize tissue survivability from stoke. We measured local cerebral metabolic rate for glucose (1 CMRglc) and an index of brain tissue pH (pHt) concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using [14C]2-deoxyglucose and [14C]dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices. Hemispheres ipsilateral to intravascular tamponade-induced middle cerebral artery occlusion showed areas of normal, depressed, and elevated glucose metabolic rate (as defined by an interhemispheric asymmetry index) after 2 hr of ischemia. Regions of increased 1 CMRglc showed moderate acidosis (6.87 +/- 0.05), while regions of normal glucose metabolic rate showed normal pHt (pH +/- SD = 6.98 +/- 0.05) and regions of decreased 1 CMRglc showed severe acidosis (6.69 +/- 0.11). A repeated-measures analysis of variance found these values to differ from each other at the P less than 0.0005 significance level. The finding of moderate acidosis coupled with increased 1 CRMglc in the metabolic penumbra suggests that the excess protons may result from the anaerobic dissociation of ATP synthesis and hydrolysis.

Spreading depolarization remarkably exacerbates ischemia-induced tissue acidosis in the young and aged rat brain

“…Our global forebrain ischemia model created conditions similar to the ischemic penumbra, in that CBF dropped below 40%, and remained between 20–40% until reperfusion was initiated 15, 37 . Prior to the detection of the propagating spontaneous SD, pHe ranged between pH 6.9–7.0 in the cortex, similar to pHi that was calculated for the penumbra region after middle cerebral artery occlusion (MCAO) 38 . Acidosis associated with SD here shifted pHe to as low as pH 6.48 in average, more typical of the ischemic core of focal insults.…”

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

“…Acidosis is a major factor contributing to cell death after cerebral ischemia (Rehncrona et al, 1981;Kraig et al, 1986Kraig et al, , 1987Siesjo, 1988;Nedergaard et al, 1991;Katsura et al, 1994). Cerebral artery occlusion produces acidosis in regions of incomplete ischemia where residual blood flow carries glucose but not oxygen, leading to anaerobic glycolysis and the production of lactic acid (Nedergaard et al, 1986;Peek et al, 1989;Obrenovitch, 1995;Swanson et al, 1997). Extracellular pH in these regions can decrease to as low as pH 6.8 to 5.9, depending on the plasma glucose concentration (Kraig et al, 1986;Smith et al, 1986).…”

The impact of aging on spreading depolarization in the intact and ischemic rat brain

“…Our global forebrain ischemia model created conditions similar to the ischemic penumbra, in that CBF dropped below 40 %, and remained between 20-40 % until reperfusion was initiated 3,83 . Prior to the detection of the propagating spontaneous SD, pHe ranged between pH 6.9-7.0 in the cortex, similar to pHi that was calculated for the penumbra region after middle cerebral artery occlusion (MCAO) 84 . Acidosis associated with SD here shifted pHe to as low as pH 6.48 in average, more typical of the ischemic core of focal insults.…”