Brain Metabolism lecture

BRAIN METABOLISMPresented by S Aryo No

High energy requirements (~10 mgkgmin)

Low energy reserves

The energy is needed to maintain the ionic gradient across nerve membranes

Brain Metabolism

Energy metabolism of the brain 2 of body weight 20 of energy

expenditure

GLUCOSE is the main fuel daily consumption 120g adopted starvation (3 weeks) oxidation of

ketones in the brain covers up to 50 of energy

Oxygen uptake Brain 20 of whole-body O2 consumption The most vulnerable to hypoxia

5 min of Ventrikel Fibrilationarrest may lead to irreversible brain damage

temperature dependent

Oxidation of non-glucose substrates ketoneslactate during prolonged fasting not in everyday life

Glucose oxidation provides more than 90 of the energy needed

Brain function almost totally dependent on a continuous supply of glucose from the arterial circulation

The source of Brain Metabolism

Insulin independent GLUT1 (55 kd form)

localized in microvessels of the blood-brain barrier Moves glucose from the capillary lumen to the brain interstitium

GLUT3 GLUT1 (45 kd form)

transport glucose from interstitium into neurons and glial cells

Upregulation in chronically hypoglycemic rats

Transport of Glucose

Glycogen---stored exclusively in glial cells (astrocytes) Metabolize to lactate that can be taken up and used as fuel by neurons

Low content in brain (~3 mmolkg) Unable to sustain brain metabolism for more than 4 to 5 minutes

Brain Metabolism

1048708What the brain does with protein DNA RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Growth factor synthesis Structural proteins

Neurite extension (axons dendrites) Synapse formation (connectivity)

1048708What the brain does with fat Cell membrane integrity Synapse formation Myelin formation

Protein and fat in the brain

Meski glukosa penting bagi otak namun kadarnya hanya sedikit

Asam amino jumlahnya 6-8 kali lbh banyak di banding di dalam darah

Asam amino asam di otak lebih banyak (aspartat dan glutamat 300x lbh banyak dibanding dg di plasma)

Kemampuan otak untuk menyimpan dan menggunakan nitrogen sangat rendah shg laju ambilan AA dari darah sangat rendah

Konsentrasi AA intrasel dlm otak tinggi (glutamat aspartat GABA) menunjukkan metabolisme AA cukup aktif

Protein metabolism

Otak mengandung lipid sederhana dan kompleks yg berfungsi untuk mempertahankan integritas membran drpd sbg senyawa metabolik

Lipid terletak pd sel dan membran sel Turn over lipid di otak rendah Kolesterol serebrosida fosfatidiletanolamin

dan sfingomielin dimetabolisme secara lambat di otak

Lipid metabolism

Liver--predominant site of glucose production Kidney--contributes minimally After 60 hours of fasting kidney contributes significantly

more (~25) through gluconeogenesis The contribution of the kidney to glucose homeostasis are

consistent with the observation of hypoglycemia in some patients with chronic renal insufficiency

Organs release glucose

Hypoglycemia plasma glucose concentration below 50 mgdL

76 -72 mgdL1048708 suppression of insulin secretion ~67 mgdL1048708 counterregulatory hormones Conservative definition plasma glucose lt75 mgdL Important to establish the lower limit of plasma glucose in

intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness

Hypoglycemia

Brain1048708 key organ for sensing hypolgycemia ldquoventromedial hypothalamusrdquo acts as a glucose sensor triggers counterregulation

Liver1048708 senses glucose concentration in the absence of counterregulatory hormones

Hypoglycemia Sensors

Hypoglycemia1048708 ventromedial hypothalamus 1048708 suppression of insulin 1048708 increase counterregulatory hormone (glucagon epinephrine1048708 growth hormonecortisol)

Architecture of Counterregulatory System

Whatacutes the first thing that happens when you think Excitatory firing Glu uptake by glia Na+

influx ATP consumption by Na-K-ATPase activation of glycolysis lactate transported to neurons

Local increase in lactate increases blood flow

Excitotoxity = excesive Glu release epilepsy traumatic brain injury Na+ and Ca2+ intra cell accumulation swelling

Functional imaging PET

Ammonia handling in the brain NH3 is a waste product of deamination

reactions (GlnGlu Glu 2-oxoglutarate etc) Metabolism

Glutamin synthetase NH3 + Glu Gln Gln is metabolized in the liverkidneys

Ammonia toxicity NH3 + 2OG + NADH Glu + NAD+ Krebs cycle impairment 2-OG depletion Glu excess excitotoxicity

Ammonia handling Clinical consequences liver disease impairs

brain function principle insufficient urea synthesis NH3

accumulationneurotoxicity Hepatic encephalopathy grI-IV Fulminant liver failure (ie paracetamol poisoning)

threatens live also by ICP

Blood brain barrier selectivity Free permeability (passive diffusion)

small molecules H2O O2 CO2 NH3 ethanol lipid soluble molecules steroid hormones

Carrier mediated transport glucose GLUT-1 (insulin independent) amino acids

Pinocytosis

Areas outside BBB Enables brain to sense and regulate blood

composition

Include Subfornical organ osmoreceptors regulate ADH OVLT dtto thirst Area postrema chemoreceptors vomiting center

BBB ndash clinical significance CNS infection

BBB protects against bacteria entry but also antibodies and antibiotics

Kernikterus hyperbilirubinemia damages the brain in

neonates but not in adults Parkinsons disease

=lack of dopamin in basal ganglia cannot be treated with dopamin (does not cross

BBB) but its precursor L-DOPA is useful

CSF in diagnostics CNS infection

bacterial meningitis viscous and opalescent CSF WBC Glucose Lac

viral meningitis few cells protein Degenerative diseases

oligoclonal bands in multiple sclerosis others

Hematologic malignancy leucemic cells infiltrate CNS