Brain levels

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

There are very limited data on the kinetics and metabolism of organotins in laboratory mammals. A widespread distribution of organotins throughout body tissues has been observed. Transplacental transfer seems to occur, whereas transfer across the blood-brain barrier is limited, since brain levels are usually low. The only compound for which data are available on metabolites is dibutyltin, which has butyl(3-hydroxybutyl)tin as its major metabolite. Limited information suggests quite rapid metabolism and elimination, with half-lives of several days. Much of an oral dose of dioctyltin was eliminated in the faeces, with the remainder in urine. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Some deaths of cormorants in the field in Holland were attributed to PCB poisoning on more substantial evidence than was available in the foregoing incident (Koeman 1972 Walker 1990a). Birds found dead had mean liver and brain levels of 319 and 190 ppm, respectively, which are not very different from those found in experimentally poisoned individuals. 

A key requirement of QSAR is that the compounds used in the modeling and prediction processes should have the same mechanism of action, and for this reason most QSAR studies are made with congeneric series of compounds. However, if a diverse set of compounds can reasonably be assumed to have the same mechanism of action, QSAR modeling can justihably be carried out. For example, Dearden et al. [43] developed a QSAR for the ratio of brain levels of 22 very diverse drugs in the wild-type mouse and the P-glycoprotein knockout mouse (R+/ ) ... 

There is a definite trend of bidirectional cross-talk between opioid and chemokine receptors in the central nervous system. In vitro, as well as in vivo studies, have shown desensitization of CXCR4 by MOR and thus prevent the neuroprotective action of this chemokine. Although the precise molecular mechanism underlying this cross-talk is still under investigation, based on the evidences in literature several possible pathways can be expected to act independently or in concert and lead to the deficit of CXCR4 function. Our studies have shown that p opioids can increase the brain levels of FHC which can subsequently block CXCR4 signaling. Eurther studies... 

There is no evidence of a general overactivity in DA function in schizophrenic patients. Plasma prolactin is not reduced, so the DA inhibitory control of its release is normal there is no recorded increase in DA turnover as CSF and plasma levels of its major metabolite HVA are normal and dyskinesias, which would reflect increased DA activity, are rare. PM studies have shown no consistent increases in DA brain levels, although some reports show an increase in the left amygdala, or in the activity of enzymes involved in its synthesis (tyrosine hydroxylase) or metabolism (MAO). For a review of the neurochemistry see Reynolds (1995). 

Functional activity (clinical effect, catalepsy in animals, etc.) is invariably correlated with plasma concentrations whereas the brain levels of many neuroleptics, which are very lipophilic compounds, could be much higher. Some clinicians also believe that many newer compounds achieve atypical status compared with older ones because they are used at minimal dosage while older ones are prescribed at established levels which may be unnecessarily high. 

Hydroxydopamine (6-OHDA) is a neurotoxin that destroys catecholaminergic neurons in the brain. This toxicity is believed to be related to the production of ROS by the neurotoxin. Rats were fed chronically with vitamin E and then challenged with 6-OHDA. The usual depletion of SOD and reduced glutathione (GSH) in most brain regions was attenuated by the vitamin E pretreatment. The authors attributed this success to scavenging by the augmented brain levels of vitamin E (Perumal et al., 1992). 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Sekerke, HJ. Smith, Fl.E. Bushing, J.A. and Sanders-Bush, E. Correlation between brain levels and biochemical effects of the optical isomers of /)-chloroamphetamine. J Pharmacol Exp Ther 193 835-844, 1975. 

In addition to the data generated from plasma samples in a standard PK study, for targets that are contained within the brain, it is also important to determine brain levels of compound, so that brain/plasma ratios can be determined. Again, these data should be correlated with in vitro assays and calculated properties such as BBB PAMPA [39]... 

But that was only one half of the logic behind the chemical-imbalance theory. The other half came from studies of reserpine, a drug that was extracted from Rauvolfia serpentina or the Indian snakeroot plant, which had historically been used to treat snakebite, hypertension, insomnia and insanity. In studies of animals, reserpine was reported to induce sedation and to decrease brain levels of norepinephrine, serotonin and dopamine. Clinical reports indicated that some people became severely depressed when taking reserpine.14 Putting these two findings together, it seemed likely that reserpine made people depressed because it decreased neurotransmitter levels. 

How is it that the chemical-imbalance theory was proposed and so widely accepted, when the only controlled scientific study that had been done indicated that one could relieve depression, rather than induce it, by giving patients a drug that increases brain levels of monoamines David Healy, in his comprehensive treatise on the history of antidepressants, provides an answer to this question.19 The study was simply ignored, despite having been published in The Lancet, one of the world s most prestigious medical journals. 

Distortion of the plasma aminogram in individuals with an aminoaciduria also may lead to a relative failure of brain protein synthesis. Thus, in mice with a deficiency of phenylalanine hydroxylase, the blood concentration of phenylalanine is more than 20 times greater than the control value, leading to partial saturation of the transport system and a diminution in the brain level of neutral amino acids other than phenylalanine. Rates of protein synthesis were concomitantly reduced [8]. 

Zinc is important to the normal functioning of the central nervous system (CNS). At low concentrations, zinc protects mammalian brain neurons by blocking N-methyl-D-aspartate receptor-mediated toxicity. At high concentrations, zinc is a potent, rapidly acting neurotoxicant in the mammalian brain, as judged by zinc-induced neuronal injury of in vitro mature cortical cell cultures (Choi et al. 1988). Increased brain levels of zinc are associated with Pick s disease in certain strains of rodents with inherited epileptic seizures. Intravenous injection of zinc in rats with genetically inherited epilepsy produces seizures a similar response occurs with intracranial injection of zinc in rabbits with inherited audiogenic seizures (Choi et al. 1988). 

Lorazepam is currently considered the BZ of choice. It takes longer to reach peak brain levels than diazepam but has a longer duration of action (12 to 24 hours). Patients chronically on BZs may require larger doses. The administration rate of diazepam and lorazepam should not exceed 5 and 2 mg/min, respectively, because the propylene glycol in the vehicle can cause dysrhythmia and hypotension. 

Biogenic amine hypothesis. Depression may be caused by decreased brain levels of the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA). 

In summary, primary amine and monoalkyl derivatives of tryptamine have not yet been demonstrated to produce hallucinogenic effects in man or to consistently produce profound behavioral effects in animals. Admittedly, relatively few compounds have been examined, and few studies have been conducted. Nevertheless, present evidence suggests that these derivatives, by virtue of their inability to penetrate the blood-brain barrier and/or their rapid metabolism, may not be able to achieve adequate brain levels to elicit effects. In some cases, these factors may lead to masking of potential central effects by peripheral actions of the compounds or their metabolites. 

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