In vivo proton MRS to quantify anesthetic effects of pentobarbital on cerebral metabolism and brain activity in rat

Abstract

To quantitatively investigate the effects of pentobarbital anesthesia on brain activity, brain metabolite concentrations and cerebral metabolic rate of glucose, in vivo proton MR spectra, and electroencephalography were measured in the rat brain with various doses of pentobarbital. The results show that (1) the resonances attributed to propylene glycol, a solvent in pentobarbital injection solution, can be robustly detected and quantified in the brain; (2) the concentration of most brain metabolites remained constant under the isoelectric state (silent electroencephalography) with a high dose of pentobarbital compared to mild isoflurane anesthesia condition, except for a reduction of 61% in the brain glucose level, which was associated with a 37% decrease in cerebral metabolic rate of glucose, suggesting a significant amount of "housekeeping" energy for maintaining brain cellular integrity under the isoelectric state; and (3) electroencephalography and cerebral metabolic activities were tightly coupled to the pentobarbital anesthesia depth and they can be indirectly quantified by the propylene glycol resonance signal at 1.13 ppm. This study indicates that in vivo proton MR spectroscopy can be used to measure changes in cerebral metabolite concentrations and cerebral metabolic rate of glucose under varied pentobarbital anesthesia states; moreover, the propylene glycol signal provides a sensitive biomarker for quantitatively monitoring these changes and anesthesia depth noninvasively. Key words: cerebral metabolic rate of glucose; CMR glc ; brain activity; brain metabolism; propylene glycol Sodium pentobarbital, one type of barbiturate, has been popularly used in clinic for treatment of seizures and preoperative sedation. It is also a common agent used for general anesthesia in clinical and animal research. Pentobarbital rapidly distributes to all tissues, with a higher concentration in brain, liver, and kidneys due to high lipid solubility. It can enhance the ␥-aminobutyric acid receptor-coupled response, thereby directly depressing neuronal excitability and resulting in an anesthesia effect in the brain and vanishing consciousness (see a recent review article, Alkire et al. (1), and references therein). The suppression of neuronal activity is also accompanied by significant depression of cerebral metabolic activity due to the inhibition of nicotinamide adenine dinucleotide (NADH) oxidation in the respiratory chain, and a deep pentobarbital anesthesia can induce a complete suppression of brain electroencephalography (EEG) activity thereby reaching an isoelectric state. Therefore, the delivery of pentobarbital into a living body can lead to a variety of brain physiologic changes, including EEG activity, cerebral metabolites/metabolic rates, and cerebral blood flow, and all these changes are expected to be related to the pentobarbital concentration reached inside the brain. It is thus essential to seek a robust, reliable tool to noninvasively assess the brain pentobarbital concentration in vivo and, ultimately, to ...

Simultaneous Measurement of Glucose Blood–Brain Transport Constants and Metabolic Rate in Rat Brain using in-vivo1H MRS

“…First, the values of CMR glc , T max , and K T determined by the dynamic post glucose infusion measurement and the standard dynamic MichaelisMenten model were 0.44 ± 0.17 mmol/g per minute, 1.35 ± 0.47 mmol/g per minute, and 13.4 ± 6.8 mmol/ L, respectively, and are in good agreement with the values reported in the literature (Brender et al, 1975;Chen et al, 1993;Du et al, 2009;Lei and Gruetter, 2006;Mason et al, 1992;Ori et al, 1986;Pardridge, 1984). Specifically, the K T value has been reported to be 13.9 ± 2.7 mmol/L from an in-vivo MRS study (Mason et al, 1992), and 11.0 mmol/L as well as T max = 1.4 to 1.6 mmol/g per minute measured by the radioactive tracer method (Brender et al, 1975;Pardridge, 1984), respectively.…”

“…This finding seemingly contradicts other studies that show a decreased brain glucose concentration accompanied by an increased CMR glc due to the elevated neuronal activity by visual stimulations (Chen et al, 1993;Mangia et al, 2007;Merboldt et al, 1992). However, this apparent discrepancy can be explained by the glucose transport regulation and plasma glucose concentration alteration, which was substantially decreased under the isoelectric condition (Du et al, 2009). A significant reduction in plasma glucose level could lead to a large decrease in brain glucose concentration, since the brain glucose concentration is tightly coupled to the plasma glucose concentration and is regulated by the glucose transport across BBB.…”

Creatine kinase and ATP synthase reaction rates in human frontal lobe measured by 31P magnetization transfer spectroscopy at 4T

“…Previous work indicated that in vivo 31 P MT provides a non-invasive approach for directly studying bioenergetics/mitochondrial function associated with brain activity changes (12–14, 24, 26). The major obstacle to this approach is the low signal-to-noise ratio (SNR) especially for ATP syn reaction measurements because of the intrinsically low nuclear gyromagnetic ratio of 31 P and the low concentration of Pi (~1mM).…”

Hyperpolarized 13 C pyruvate mouse brain metabolism with absorptive-mode EPSI at 1 T

“…For this reason, extrapolation of the metabolic parameters to humans is guarded. Further, we imaged mice under anesthesia, which is known to alter brain metabolic profiles [31,32]. The quantitative parameters in this work are thus relative and not absolute.…”