Nervous tissue properties

These families are defined by individual members, which are related to each other by common primary sequences, structural motifs and binding properties (e.g. Fig. 7-1). In spite of differences in the biochemistry and function of each CAM, we can make certain generalizations about how they function in nervous tissue. First, CAMs act at... 

Tourneur,Y. and Vignon, J. Identification and properties of phencyclidlne-bindlng sites in nervous tissues. Fed. Proc. Fed. Am. Soc. Exp. Biol. 42 2570-2573, 1983. 

The Rhodonines, when in the liquid crystalline state, are complete chromophores. They need not be associated with any other material to accomplish the absorption process. When still suspended in a liquid medium, they will not, as a large group, display any unique polarization properties. If they are brought to an ever higher level of concentration in a liquid, they will form a gel which will exhibit preferred polarization planes. They can also be precipitated onto a surface after which they will exhibit preferred planes of polarization. They can be precipitated onto glass as well as a protein substrate. They must, of course, be associated with some type of nervous tissue in order to generate the necessary nerve signals. This is clearly not a role for opsin, defined as a protein, to play. 

The structure of chemicals and their differential access to the nervous system are of critical importance in determining the presence and nature of the neurotoxic response. While access to nervous tissue dictates the possibility of a direct neurotoxic effect, neurotoxicity ultimately depends on the ability of the substance to bind to neural tissue targets and interfere with functional or structural integrity. Structure-activity relationships are therefore of cardinal importance. For example, 1,2-diacetylbenzene but not 1,3-diacetylben-zene induces leg weakness because only the former binds to and crosslinks neuroproteins. Triethyltin targets the myelin sheath, trimethyltin damages neurons, but tributyltin lacks neurotoxic properties - another illustration of the critical importance of chemical structure in determining the presence and nature of the neurotoxic response. 

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. 

Historically, measurements of the isozymes of creatine kinase (CK) and lactate dehydrogenase (LD) have been used for the detection of myocardial injury. These are enzymes of intermediary metabolism found in both cardiac and skeletal muscle, although in different forms reflecting the different metabolic and functional properties of these tissues. There are also significant amounts of CK in nervous tissue and smooth muscle, whereas LD is expressed in most tissues (Aktas et al. 1993). 

Only few studies have been conducted to analyze the toxicokinetic properties of types I and II in laboratory animals [27-29]. The lipophilicity of pyrethroids also enables rapid access to tissues, including the CNS. Non-cyano pyrethroids (permethrin) as well as cyano pyrethroids (deltamethrin and cyhalothrin) have an accumulation in the nervous tissues [25, 28, 29]. The toxicokinetic behavior of these pyrethroids revealed prolonged elimination half-lives (typically in the order of 10 h but may be larger) and high concentrations in several regions of the brain... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

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