Alterations at cellular level

Many of the enzymatic reactions of neurons, glial cells, and specialized cerebral capillary endothelium in the brain must be catalyzed by the energy-yielding hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate. Without a constant and generous supply of ATP, cellular synthesis slows or stops, neuronal functions decline or cease, and cell structures quickly fall apart. The brain depends entirely on the process of glycolysis and respiration within its own cells to provide its energy needs. The oxygen-requiring process of respiration is more efficient than glycolysis in generating the energy needs of the brain. The enzymes of the glycolytic pathway can increase their rates only about sixfold; glycolysis alone is unable to meet the energy needs of the human brain, even if the circulation and other support systems could sustain an increase in the delivery of glucose. This insufficiency in glycolytic enzymatic action explains the constant need for oxygen to ensure appropriate cerebral function. Even a short interruption of blood flow or oxygen supply threatens tissue vitality ( Plum and Posner. ..1982).

During anoxia, the level of ATP rapidly decreases to near zero. This causes an increase in glutamate, an excitatory amino acid, which acts through the W-methyl-D-aspartate (NMDA) receptor and finally leads to high levels of free intracellular calcium [Ca 2+]h The addition of 2-deoxyglucose to cells, which acts as an ATP sink, causes a rapid increase in [Ca2+]h activating phospholipase A2 which breaks down membrane phospholipids into free fatty acids, particularly arachidonic acid. This causes increased activity of the cyclo-oxygenase pathway producing prostaglandins (including thromboxane A 2), the lipoxygenase pathway producing leukotrienes, or both. Furthermore, the hydrolysis of ATP via AMP leads to an accumulation of hypoxanthine. Increased [Ca 2+] enhances the conversion of xanthine dehydrogenase to xanthine oxidase, priming the neuron for the production of the oxygen free radical O 2- intracellularly, once O2 is reintroduced during reperfusion (Safar... and... .Bircher.1988).

In hypoglycemia loss of substrate leads to increased metabolism of endogenous substrates in the brain, membrane depolarization, energy depletion, and increased levels of intracellular calcium. The neuronal injury and death induced by sustained glucose deprivation also result in part from the neurotoxic effects of glutamate, acting through NMDA receptors to stimulate the cellular uptake of calcium and to activate lipases, in a manner analogous to the mechanism of anoxic neuronal injury.

The development of coma in hepatic encephalopathy has been attributed to high blood levels of ammonia, alterations of the plasma amino acid profile (increased levels of branched-chain amino acids and decreased levels of aromatic amino acids), release of false neurotransmitters (octopamine and phenylethanolamine), and activation of the GABA system. Recent experimental studies of septic encephalopathy suggest also involvement of the GABA system.

In patients with diabetic ketoacidosis impaired consciousness is assumed to be due to increasing extracellular hydrogen ion concentration, followed by reduced oxygen consumption and decreased glycolysis in brain cells. In hyperosmolar non-ketotic diabetic coma, osmotic diuresis leads to exsiccation and neuronal dehydratation, thereby reducing cerebral cellular metabolism. Hypernatremia causes neuronal dehydratation with consecutive rupture of the vessels. When it develops slowly, this cellular dehydratation could be balanced by the synthesis of 'idiogenic' osmotic substances (amino acids, particularly taurine). Acute hyponatremia can cause brain swelling when water moves from plasma to brain, lowering brain osmolality to match that of the hypotonic plasma. Hyponatremic brain edema is normally prevented by the transport of osmotically active solutes out of the brain cells by processes involving the Na +, K+-ATPase pump, amino acids, and the calcium channels. This preventive mechanism may be altered in premenopausal women and hypoxia.

In uremia increased permeability of cell membranes allows circulating organic acids access to the brain and causes an alteration in mental status. In addition, the cerebral oxygen consumption declines, glycolysis and energy utilization are reduced, and the sodium and potassium flux is decreased ( Plum a.n.d P.o,s.n§r..1.982.).

Myxedema coma and thyroid storm can also cause alterations in consciousness by decreasing or increasing cerebral oxygen consumption and the synthesis of nucleoprotein and protein in neurons and synapses ( Plum and P.o.s.n.e.r 1..9.82).

Hyperthermia (body temperature above 40 °C) has a direct toxic effect on brain and consciousness by denaturing cellular enzymes and therefore leading to cell death, cerebral edema, and local hemorrhage. Hypothermia (body temperature below 30 °C) also has a severe impact on cerebral function by reducing the cellular metabolism until irreversible structural damage occurs (RippeetaL 1991). In head injury an initial impact produces several degrees of mechanical neuronal and axonal damage. Secondary lesions occur as a consequence of elevated intracranial pressure due to cellular edema and hypoxic cell injury ( Tin.ti.Di!!.! eLaL 1992).

Many drugs in common use must be considered as causes of unconsciousness. Alcohol intoxication may lead to impaired consciousness by depressing cerebral activity due to interference with ion transport at the cell membrane rather than the synapses. Barbiturates mediate their effect through the inhibitory GaBa synapses of the brain and thus interfere with cerebral oxidative enzymes and depress cellular metabolism. Tricyclic antidepressants reduce the production of serotonin and norepinephrine (noradrenaline) in the cerebral fluid. They are also competitive antagonists of the muscarinic acetylcholine receptors and much of the central nervous system toxicity is an exaggeration of the central and peripheral side-effects. Benzodiazepines attach to the polysynaptic terminals where GABA is released, cause hyperpolarization, and therefore potentiate the GABA effect. Opiates (synthetic and natural) produce a number of clinical effects that are also induced by endogenous morphine-like substances (endorphins), as well as substances in related groups (encephalins and dynorphins), acting on specific neurons. In these neurons different receptor sites may be present, of which the m, k, and s receptors appear to be associated with the opioid action. The main effect of opiates is mediated by the m receptor, whose stimulation has a central depressant effect (E!!e.Dh° B.a.rce.lo.u.xJSSS).

Postconvulsive coma may occur after seizures and is mediated by neuronal damage due to both increases in neuronal metabolic demand and decreases in energy supply. The degree of hyperthermia during an episode of seizure seems to be correlated with the degree of neuronal damage ( Rippe...§LaL 1991). In cerebral infection, coma may be caused by hypoxia due to vascular damage, increased cerebral pressure due to cell edema, and energy deficiency due to competition with micro-organisms for nutrients.

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