Nervous system perturbation

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

Incidents of vincristine overdosage have been reported relatively frequently in the medical literature. Some of these have involved inadvertent administration of the intravenous formulation into the central nervous system by the intrathecal route this produces devastating results by a combination of chemical damage to sensitive neuronal tissue as well as biochemical perturbations. Two representative cases of vincristine overdose were described (46) involving administration of vincristine to patients scheduled to receive vinblastine. In one patient toxicity initially involved vomiting and diarrhea with subsequent constipation and paralytic ileus (inhibition of motor activity in the small intestine). Muscle pain... 

The four mechanisms listed above involve direct interaction of a toxicant with a receptor in such cases, the toxicant-receptor interaction is likely to be involved in the mechanism of action. In many cases, toxicants may affect receptor function indirectly. For example, in the nervous system, decreases in synaptic transmission (by receptor blockade or damage to a neuron) may lead to increases in the number of receptors on the target neuron (so-called upregulation). This is often felt to be one of the compensatory mechanisms by which the nervous system responds to such perturbation. Conversely, increases in synaptic transmission (e.g., by long-term receptor activation) may lead to compensatory decreases (downregulation) in receptor number. The techniques by which such mechanisms are studied are described later in this chapter. It should be noted that the availability of molecular probes now permits evaluation not only of the characteristics of the binding sites, but also of the expression of the mRNA for the receptor(s) under study. 

Halohydrocarbon solvents containing an acidic C—H bond shift this equilibrium in favour of free or less associated species, thus perturbing the ion channels which determine the permeability of neuron membranes to K /Na ions in the nervous system. Hydrogen bonds play a decisive role in determining the structure and dimension of these ion channels, on which this permeability depends [300],... 

A. Valproic acid is a low-molecular-weight (144.21), branched-chain carboxylic acid (pKg = 4.8) that increases levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and prolongs the recovery of inactivated sodium channels. These properties may be responsible tor its action as a general central nervous system depressant. Valproic acid also alters amino acid and fatty acid metabolism with dismption of the urea cycle, and can cause hepatotoxicity, metabolic perturbations, cerebral edema, and bone marrow depression. Some of these effects may be associated with carnitine deficiency. 

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