CEREBRAL BLOOD FLOW AND METABOLISM

Transcription

1 Supported by: HURO/0901/069/2.3.1 HU-RO-DOCS CEREBRAL BLOOD FLOW AND METABOLISM Part 11.

2 Cerebral blood flow Supplies cerebral metabolism demanded by neuronal function Is required for the production and absorption of the cerebrospinal fluid (CSF) Transports hormones produced in the brain or delivers hormones regulating brain function What are the demands of cerebral metabolism?

3 Cerebral energy metabolism Glucose plays central role as an energy substrate in the brain Aerobic oxidation Cerebral Metabolic Rate of glucose (CMR glc ) µm/min/100g Cerebral Metabolic Rate of oxygen (CMR O2 ) ml/min/100g

4 The aerobic oxidation of glucose Glucose + 6 O 2 6 CO 2 +6 H 2 O+ 36?ATP In fact, the measured CMR O2 /CMR glc 5.5 and the respiratory quotient of the brain RQ=VCO 2 /VO 2 1

5 Additional uses of glucose Pentose-phosphate shunt (2-5% of CMRglc) - produces NADPH coenzyme for many enzymes Synthesis of glycolipids and glycoproteins glycogen synthesis (astroglia) Amino acid synthesis: Ser, Gly, Ala, Glu, Gln

6 Additional uses of oxygen Cyclooxygenase prostanoid synthesis tyrosin-hydroxilase catecholamin synthesis monoamino-oxidase biogenic amin degradation NO-synthase NO-synthesis Heme-oxygenase - CO-synthesis NADPH-oxidase

7 Cerebral energy metabolism Glucose + 6 O 2 6 CO 2 +6 H 2 O+ 36?ATP CMRO 2: ~50ml/min, 20% of O 2 consumption at rest Cerebral blood flow has to deliver daily: ~72 liters of O 2, ~ 3 M ~0.5 M ~100g glucose, CBF simultaneously has to carry away ~72 liters of CO 2, ~3M ~50 ml metabolic water and ~1500 kj thermal energy (21.2kJ/l O 2 )

8 Glucose transport in the brain all cell types express facilitative glucose transporters of the GLUT family GLUT 1 is responsible for the transcellular transport of glucose through the blood brain barrier

9 Neuron-glia-capillary interactions in glucose metabolism

10 Alternative energy substrates Ketone bodies: in fetal life and at prolonged fasting may contribute 50% of energy production Fatty acids: especially in infants while breastfeeding (maternal milk diet) Lactic acid?

11 The ketone bodies Acetone Acetoacetic acid b-hydroxybutiric acid

12 Ketone bodies are transported via facilitative monocarboxylate transportes (MCT) Journal of Cerebral Blood Flow & Metabolism (2007) 27, ;

13 Difficult task: getting rid of metabolic water Neurons produce ~12 times more water than the average cell Their membrane does not contain many aquaporins (water channel proteins) They must rely on molecular water pumps (MWPs) to get rid of the water MWPs operate through cycling of hydrated molecules

14 NAA a likely MWP Acetyl-CoA + Aspartate N-acetyl-aspartate (NAA) synthesized in neurons in high concentration (~20 mm!) synthesis is coupled to glucose metabolis degraded in glial cells, acetate and aspartate recycles to neurons NAA one cycle removes ~ 120 water molecules

15 NAA as an MWP of neurons Neuron Glia Aspartate + Ac-CoA Aspartate + Acetate NAA+ nh 2 O NAA+ nh 2 O Aquaporin nh 2 O n~120

16 Metabolic water is drained towards the cerebrospinal fluid filtrate lymph Metabolic water

17 Additional requirements of cerebral metabolism Amino acids required for protein synthesis Excretion of ammonia derived from amino acid degradation Essential, polyunsaturated fatty acids required for membrane synthesis Vitamins, iron Prevent the uptake of any endo- or exogenous substance present in the blood plasma that can potentially interfere with neuronal function

18 T3/T4 Smith QR J Nutr 130: S (2000)

19 Additional requirements of cerebral metabolism Amino acids required for protein synthesis Excretion of ammonia derived from amino acid degradation: GLUTAMINE secretion Essential, polyunsaturated fatty acids required for membrane synthesis Vitamins, iron Prevent the uptake of any endo- or exogenous substance present in the blood plasma that can potentially interfere with neuronal function

20 Glutamate/glutamine transport across the blood-brain barrier primarily serves cerebral ammonia homeostasis (daily glutamate uptake ~8g, glutamine secretion ~12 g)

21 Summary of cerebral blood flow regulation METABOLIC AUTOREGULATION CBF CBF Local! (low) (high) Neuronal activity Perfusion pressure CBF CHEMICAL CO 2 CBF EXTRINSIC NEUROGENIC (alkalosis) brain ECF pco2 (acidosis) sympathetic stimulation

22 Neuronal activation and local CMRglc are tightly coupled Studies with 2-deoxy-D-glucose: first auroradiographic CMRglc and CBF determinations followed by positron emission tomography

23 Cerebral metabolic rate of glucose (CMRG) PET maps during different task, in man

24 CBF PET map during stimulation of the right visual field, in man

25 PET and MRI (green: foot, red: hand, pink tongue movements

26 Flow-metabolism coupling LOCAL increases in neuronal activtity lead to local increases in metabolism eliciting arteriolar vasodilation and LOCAL increases in blood flow This is in fact an active (functional) hyperemia First proposed by Roy and Sherrington (1890) The most important physiological regulatory mechanism

27 Factors determining cerebral blood flow Under physiological circumstances, CBF is regulated through the local control of arteriolar diameter

28 The neurovascular unit Morphological and functional unit of all cell types responsible for the metabolic homeostasis of the brain Microvascular cells: endothelium, vascular smooth muscle, pericytes Parenchymal cells: astrocytes, neurons

29 Proposed mechanisms of flow-metabolism coupling in the neurovascular unit Neurology 2007;68:

30 Mechanism of flow-metabolism coupling hypoxia, hypercapnia, and hypoglycemia DO NOT develop during coupling Neuronal and glial factors can affect the vascular smooth muscle metabolites: K +, lactate, adenosine problem with metabolites: coupling is faster than their release local vasoactive mediators: prostaglandins, NO, EET-s

31 Extrinsic and intrinsic innervation of blood vessels affect the neurovascular coupling Hamel, E. J Appl Physiol 100: ; doi: /japplphysiol

32 Summary of the regulation of cortical microvessels from cells located in subcortical areas and within the cerebral cortex Hamel, E. J Appl Physiol 100: ; doi: /japplphysiol

33 Mechanism of flow-metabolism coupling hypoxia, hypercapnia, and hypoglycemia DO NOT develop during coupling Neuronal and glial factors can affect the vascular smooth muscle metabolites: K +, lactate, adenosine problem with metabolites: coupling is faster than their release local vasoactive mediators: prostaglandins, NO, EETS Intrinsic innervation may modify the local function of the neurovascular unit, special local coupling neurons? (VIP, NO)

34 Increases in blood flow and glucose transport rate occur simultaneously in the neurovascular unit upon neuronal activation!

35 Cellular elements of the neurovascular unit