Presented by: S Aryo No

High energy requirements (~1.0 mg/kg/min) Low energy reserves

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

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

Brain: 20% of whole-body O2 consumption The most vulnerable to hypoxia

5 min of Ventrikel Fibrilation/arrest may lead to irreversible brain damage temperature dependent

Oxidation of non-glucose substrates:

ketones/lactate 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.

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.

 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 mmol/kg). Unable to sustain brain metabolism for more than 4 to 5 minutes.

 What 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)

What the brain does with fat

Cell membrane integrity Synapse formation Myelin formation

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

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

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.

Hypoglycemia: plasma glucose concentration below 50

mg/dL
76 -72 mg/dL suppression of insulin secretion ~67 mg/dL counterregulatory hormones

Conservative definition: plasma glucose <75 mg/dL

Important to establish the lower limit of plasma glucose in intensive therapy to prevent recurrent hypoglycemia and hypoglycemia unawareness.

Brain key organ for sensing hypolgycemia. ventromedial hypothalamus acts as a glucose sensortriggers counterregulation
Liver senses glucose concentration in the absence of counterregulatory hormones.

 Hypoglycemia ventromedial hypothalamus suppression of insulin increase counterregulatory hormone (glucagon/ epinephrine growth hormone/cortisol)

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

NH3 is a waste product of deamination reactions (GlnGlu, Glu 2-oxoglutarate etc.) Metabolism:
Glutamin synthetase: NH3 + Glu Gln Gln is metabolized in the liver/kidneys

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

Clinical consequences: liver disease impairs brain function

principle: insufficient urea synthesis NH3 accumulationneurotoxicity Hepatic encephalopathy: gr.I-IV Fulminant liver failure (i.e. paracetamol poisoning) threatens live also by ICP

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

Enables brain to sense and regulate blood composition Include:

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

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

CNS infection
bacterial meningitis: viscous and opalescent CSF, WBC, Glucose, Lac viral meningitis: few cells, protein oligoclonal bands in multiple sclerosis others

Degenerative diseases

Hematologic malignancy
leucemic cells infiltrate CNS