Nervous tissue inhibitors

The toxic organic phosphorus compounds act as powerful inhibitors of cholinesterase, an enzyme found predominantly in the nervous tissue of animals, including insects. This enzyme hydrolyzes acetylcholine, which plays an essential role in the transmission of nerve impulses. The toxicity of compounds in this series can be largely accounted for on the basis of their anticholinesterase activity (7,8,12,14, SI). 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

Disulfoton causes neurological effects in humans and animals. The mechanism of action on the nervous system depends on the metabolism of disulfoton to active metabolites. The liver is the major site of metabolic oxidation of disulfoton to disulfoton sulfoxide, disulfoton sulfone, demeton S-sulfoxide and demeton S-sulfone, which inhibit acetylcholinesterase in nervous tissue. These four active metabolites are more potent inhibitors of acetylcholinesterase than disulfoton. Cytochrome P-450 monooxygenase and flavin adenine dinucleotide monooxygenase are involved in this metabolic activation. The active metabolites ultimately undergo nonenzymatic and/or enzymatic hydrolysis to more polar metabolites that are not toxic and are excreted in the urine. 

Isoniazid reacts with pyridoxal phosphate to form a hydrazone (Fig. 7.42), which is a very potent inhibitor of pyridoxal phosphate kinase. The hydrazone has a much greater affinity for the enzyme (100—lOOOx) than the normal substratepyridoxal. The result of this is a depletion of tissue pyridoxal phosphate. This cofactor is of importance particularly in nervous tissue for reactions involving decarboxylation and transamination. The decarboxylation reactions are principally affected however, with the result that transamination reactions assume a greater importance. 

However, even erythrocyte AChE measurements cannot be expected to be a perfect surrogate for the nervous tissue enzyme this is because pharmacokinetic factors may result in differential access of the inhibitor to the red cell and to neural structures. A further consideration is that, where nerve agents react with the enzyme to produce a phosphonylated structure that does not spontaneously reactivate, red cells of mammals lack the protein synthetic capability to synthesize new AChE. By contrast, in nervous tissue, after inhibition by OPs whose enzyme-inhibitor complex with AChE does not readily reactivate, activity may reappear relatively quickly. Thus, Wehner et al (1985) observed approximately 30% recovery after 24 h in di-isopropylfluorophosphate (DFP)-treated mouse CNS reaggregates, which was clearly due to synthesis de novo of AChE. Another consideration in the interpretation of butyrylcholinesterase activity measurements is that the normal range is relatively wide, rendering interpretation in individual patients difficult unless the results of previous estimations in the patient are available (Swami-nathan and Widdop, 2001). 

More elegant analytical methods exploit substances biological or biochemical properties. This is simple for acetylcholinesterase-inhibiting pesticides. Acetylcholinesterase is easy to measure, and the enzyme may be bought from suppliers or extracted from flies, earthworms, or vertebrate nervous tissue. The enzyme may be measured with and without addition of the extract containing the insecticide. Some plant materials may contain natural cholinesterase inhibitors (e.g., solanine in potato) that will interfere with this analysis if not removed. 

The nerve gases are powerful inhibitors of the enzyme acetylcholinesterase (AChE), which causes rapid hydrolysis of acetylcholine. They are also inhibitors of butyryl-choUnesterase and carboxylesterase. Acetylcholine is the chemical that is released to transmit nerve impulses in the central nervous system and also at several peripheral locations. Once the impulse is transmitted, acetylcholine must be removed instantaneously for proper functioning of the nervous system. Such removal is done by the enzyme AChE, which is found extensively in nervous system and many non-nervous tissues. Nerve gases and other organophosphorus compounds bind... 

Reductase. The polyols are accumulated in nervous tissue (the nerve cell membrane is not permeable for polyols) causing osmotic damage to the nerve cell with reduction in myo-inositol and Na+/K+-ATPase activity and increased oxidative stress. A number of Aldose Reductase inhibitors have been developed, and several of these have been tested in diabetic patients [6]. 

NO produced by NOS 1 is an important modulator of nervous tissue cell apoptosis. Andoh and colleagues noted that NOSl influences Bcl-2 and other apoptosis regulators, and accounts for some of the neural cell resistance to apoptosis of preconditioning stress (Andoh et al. 2000). Others showed increased NOSl in dorsal root ganglion neurons, as well as an NO inhibition of Bax, caspases, and apoptosis (Thippeswamy et al. 2001). NOSl is found in normal hematopoietic cells, and it influences proliferation and differentiation of these cells (see below) (Enikolopov et al. 1999 Krasnov et al. 2008 Michurina et al. 2004). NOS 1 is expressed in human CLL cells, and NOSl inhibitors induce apoptosis and death in these cells (see below for further discussion of this) (Levesque et al. 2008). 

Gardner J, Ghorpade A (2001) Tissue inhibitor of metalloproteinase (TIMP)-l the TIMPed balance of matrix metalloproteinases in the central nervous system. J Nemosci Res 15 801-806... 

The answer is c. (idardman, p 510.) Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase. It cannot readily penetrate the central nervous system (CNS) and, thus, decreases the decarboxylation of L-clopa in the peripheral tissues. This promotes an increased concentration of L-clopa in the nigrostriatum, where it is converted to dopamine. In addition, the effective dose of L-dopa can be reduced... 

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