Nerve agents direct nervous system effects

V. DIRECT CENTRAL NERVOUS SYSTEM EFFECTS OF CWAs AND STRESS A. Acute Exposure to Nerve Agents... 

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Although there is the potential for nerve agents to have direct toxic effects on the nervous system, there is no evidence that such effects occur in humans at doses lower than those causing cholinesterase inhibition. For the purpose of evaluating potential health effects, inhibition of blood cholinesterase is generally considered the most useful biological endpoint. 

AH of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. 

Although these electrophysiological data indicate that nerve agents may have direct effects on the nervous system unrelated to AChE inhibition, the data do not provide a means of determining a dose conversion to an integrative whole-body endpoint such as lethality or quahtative/... 

Certain neurotoxicants act by directly influencing the electrical activity of the insect nerve membrane through a specific action at ion-selective channels. These phenomena can be studied using many of the neurobiochemical techniques that have successfully been applied to vertebrate nervous systems. In this study we use the technique of insect synaptosomes in superfusion to examine the interaction of a range of insecticidal agents with ion channels in the nerve terminal by monitoring effects on transmitter release. 

Cesium exhibits marked effects on the nervous system, both peripherally and centrally. This may be the consequence of the purported interchangeability of cesium with other group I metals. Certainly cesium ions will increase the frequency of miniature end-plate potentials, thought to be due to the slow entry of cesium ions into the nerve terminal [32]. In the central nervous system, it seems that cesium can share the same receptor as glycine and exerts its effects by activating the same chloride channel as the inhibitory neurotransmitter, glycine [33]. Indeed, in consequence of this action, cesium has been implicated as a causative agent of some epileptiform seizures [34]. More recently, pretreatment of rats with cesium chloride, followed by administration of the monoamine oxidase inhibitor tranylcypramine, has been shown to enhance 5-hydroxytryptamine (5-HT) behavioral syndrome. This may be due to either an increased amount of 5-HT synthesis and/or release, or a direct enhancement of the postsynaptic action of 5-HT [34b]. 

Toxic agents which affect the peripheral nervous system do so through effects on the synapses of both the autonomic and voluntary systems and by direct actions on peripheral nerves. Military examples include nerve agents and toxins. Civil examples include pesticides and many marine and animal toxins. 

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