Drug-Induced Neurological Disorders
Drug-Induced Neurological Disorders
Sequelae of Disturbances of Brain Energy Metabolism Sequelae of metabolic disturbances of the brain are: Ca2+ entry into neurons, free radical formation, and excitatory amino acids.
Ca2+ Entry in Neurons
Ca2+ normally acts as a second messenger and plays an important role in membrane stabilization and regulation as well as neurotransmitter release. However, it can also cause cell death under certain circumstances. Ca2+ enters the postsynaptic neurons mostly through receptor operated calcium channels which lie on dendrites. The most important transmitters are glutamate and related amino acids. The best known is N-methyl-D-aspartate (NMDA) receptor linked to calcium channels. Stimulation of this receptor allows mainly Ca2+ and some Na+ to enter the cell. Inside the neuron Ca2+ is a signal which is changed into various cell responses. During energy deficit Ca2+ may rise manifold and set off metabolic reactions with formation of free fatty acids (FFA) and cell destruction. Increased level of Ca2+ in mitochondria activates various dehydrogenases and alters the metabolic flux into the citric acid cycle. Cell viability is threatened when calcium homeostasis fails and calcium-activated reactions run out of control. There is considerable evidence for a link between Ca2 influx and neuronal necrosis.
A free radical is an agent with an unpaired electron in its orbit. Oxygen radicals are produced by normal cellular metabolism but are usually kept under control by several defense mechanisms. Such defense mechanisms may be overwhelmed when there is increased production of oxygen free radicals by hypoxia and disturbance of cellular metabolism. The central nervous system is particularly vulnerable to free radical damage because of its high lipid content.
Superoxide radical is water soluble but it can cross membranes through the anion channels and enter the extracellular space. Seizures are one manifestation of the attack of free radicals on neuronal membranes. Drug-induced seizures lead to increase of brain levels of FFA. Superoxide may arise from further metabolism of FFA. Oxygen radicals may also increase the permeability of BBB. Free radical mechanisms may contribute significantly to the expression of harmful properties of diverse, unrelated neurotoxic agents.
Excitatory Amino Acids
Current evidence suggests that poorly controlled release of these amino acids, their insufficient clearance from the extracellular space and the breakdown of surrounding GABA-ergic inhibition transform the excitatory transmitters into potential toxins. Pathogenesis of excitotoxic cell damage is shown in Figure 2.1.
Mitochondrial DNA is susceptible to mutations by endogenous as well as exogenous factors. Increased sensitivity to mutagenic factors may account for the mitochondrial DNA polymorphism within ethnic groups and mitochondrial disease associated with all mitochondrial DNA mutations, including DNA depletion. Mitochondrial damage is known to be caused by classic poisons such as cyanide and carbon monoxide.
Neurotransmitter disturbances are an important pathomechanism of adverse reactions of several drugs such as antidepressants which are aimed at manipulating this system for therapy. Some neurotransmitters involved in DIND are: serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh).
Both excess and depletion of this neurotransmitter can produce neurological disorders. Examples of drugs which produce depletion of serotonin are substituted amphetamine derivatives: 3,4-methylenedioxyamphetamine (MDMA), ecstasy, P-chloramphetamine (PCA), and fenfluramine.
All of these drugs release serotonin and cause depletion of 5-HT from most axon terminals in the forebrain. Decrease in brain levels of serotonin are considered to be due to drug-indu