Regulation Of Cerebral Metabolism Research Articles

Abstract WP148: The Effect of Mitochondrial Migration From Astrocyte to Glial Cells Under Prolonged Cerebral Hypoperfusion

Introduction: Astrocytes play broad roles in the Central nervous system, and are involved in the regulation of cerebral metabolism and blood flow. Normal astrocytes (A2) protect against oxidative stress and excitotoxicity, but unhealthy astrocytes (A1) may release deleterious factors. Oligodendrocytes (OLGs) differentiate from oligodendrocyte-precursor-cells (OPCs) for myelination in white matter, but OPC were vulnerable for ischemia. Therefore, differentiation is impaired when white matter injury occurs in a chronic cerebral hypoperfusion model. Thus, we examined the effects of the interaction between astrocyte and oligodendrocyte lineage cells on myelination focused on mitochondrial migration. Method: A microcoil was applied to the bilateral common carotid arteries in male C57BL/6 mice as an in vivo cerebral chronic hypoperfusion model (BCAS model). A nonlethal concentration of CoCl 2 was added to the primary cell culture from the postnatal rat cortex and incubated in vitro. Results: White matter injury progressed in the BCAS model as myelin decreased. The numbers of OPCs and astrocytes increased after the operation, whereas that of OLGs decreased at day 28. Increased astrocytes were mainly A1 type, and A2 type were decreased. OPC differentiation was disrupted under the stressed conditions in the cell culture, but improved after administration of astrocyte-conditioned medium (ACM), but injured ACM couldn’t improve maturation. Incubate with CoCl 2 change astrocyte A2 to A1, and mitochondrial migration also reduced. Trkβ agonist could change astrocyte A1 to A2 even in hyperperfused condition, and also help OPC maturation via mitochondrial migration and drug effect in vivo and in vitro. Conclusions: The reduction in incrementing A1 astrocytes protect white matter injury. and Trkβ agonist may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration could be a broad therapeutic strategy for cerebrovascular disorders.

Regulation of cerebral metabolism during cortical spreading depression

We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels <3, the major part (>90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.

Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids.

The transport of neutral amino acids through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, is an important control point for the overall regulation of cerebral metabolism, including protein synthesis and neurotransmitter production. The Michaelis-Menten kinetics of BBB amino acid transport have been investigated in vivo with the brain uptake index (BUI) technique, and in vitro with the isolated human brain capillary preparation. The only amino acid that is albumin-bound is tryptophan, and the majority of albumin-bound tryptophan in the plasma is available for transport through the BBB via an enhanced dissociation mechanism that operates at the surface of the brain capillary endothelium. The availability in brain of amino acids is predicted from the BBB Km values to be sharply influenced by supra-physiological concentrations of phenyalanine in the 200-500 microM range. Moreover, the measurement of cerebral protein synthesis with an internal carotid artery perfusion technique and HPLC-based measurements of aminoacyl-transfer RNA specific activities shows an inverse relationship between cerebral protein synthesis and plasma phenyalanine concentrations in the 200-500 microM range. These findings indicate the neurotoxicity of hyperphenylalninemia is not restricted to the phenylketonuria range of approximately 2000 microM, but is exerted in the supra-physiological range of 200-500 microM.

Cerebrovascular sensory innervation involved in the development of cerebral vasospasm following a subarachnoid hemorrhage

Cerebral vasospasm following subarachnoid hemorrhage was induced in the squirrel monkey in order to evaluate the involvement of cerebrovascular sensory nerves in the development of the vasospasm. A unilateral surgical section of the trigeminal nerve at post- but not at pre-Gasserian level caused constriction of the major ipsilateral cerebral arteries. A pre- or postganglionic trigeminal lesion induced an increased glucose uptake globally without influencing the cerebral blood flow. Following a subarachnoid hemorrhage, the decrease in cerebral blood flow was similar of that seen in control animals, while post-ganglionically lesioned animals had an additional increase in glucose uptake. Intrathecal injection of γ-globulin against substance P prevented the occurrence of vasospasm and the decease in cerebral blood flow, while calcitonin gene-related peptide (CGRP) anti-γ-globulin injection significantly reduced the resting vessel diameter and did not influence spasm development. It is concluded that a nervous reflex mechanism could underlie cerebral vasospasm. The cerebrovascular sensory nerves have both a peripheral and a central function. A peripheral or axon reflex mechanism exerts a tonic effect on the cerebral arteries. Central neurotransmission seems to be involved in the regulation of cerebral metabolism and possibly in the coordination of cerebral blood flow and glucose metabolism. CGRP could be the transmitter involved in a peripheral axon reflex and substance P might be the neurotransmitter conveying information to the brainstem vascular centers.

Effect of pre- and postganglionic lesioning of the trigeminal nerve on cerebral blood flow and glucose metabolism following a subarachnoid haemorrhage in the squirrel monkey.

Simultaneous cerebral blood flow (CBF) and glucose metabolism (CMRglu) studies with a double isotope autoradiographic technique were applied to squirrel monkeys submitted to a unilateral pre- or postganglionic trigeminal lesion. The CBF values were not affected following a pre- or postganglionic lesion per se. In contrast, there was a global increase in the cerebral glucose uptake of about 50% as compared to controls following both kinds of lesions. Following a subarachnoid haemorrhage (SAH) 2-4 weeks after pre- or postganglionic trigeminal lesioning, there was a decrease in CBF similar to that seen in the control group. In the animals with a preganglionic lesion, the 50% increase in glucose uptake was not further augmented by a SAH and the increase in CMRglu was comparable to that found in control SAH animals. In the postganglionically lesioned monkeys, a SAH induced an additional increase in glucose uptake of about 50%. The findings suggest that the trigeminal system is involved in the regulation of cerebral metabolism via a brainstem centre.