Human brain AChE inhibition

However, as illustrated in Fig. 19, the magnitude of brain AChE inhibition is clearly age- and dose-dependent, and although dramatically inhibited in neonatal rats (lOmg/kg response), the adults appear to be refractory to any AChE inhibition at these same dose levels. Although these simulations illustrate the ability to scale age-dependent changes within a species, the different time scales between development in neonatal animahs and human infants create uncertainty in extrapolation across species (Ginsberg ct uL, 2004). 

Fig. 6. Summarization of results correlating inhibition efficacy (piso) and toxicity (log LD50) for some OP and nerve agents. Equation y = 9.87 — 1.26x p < 0.01 rxy = —0.9489. The lines indicate experimentally determined piso (human brain AChE) values (axe y) or extrapolated values (axe x) of LD50 for systox and VX. Each point represents the value of piso corresponding to LD50 value for rabbit, rat, guinea pig, mouse, and dog. The compounds under code are designated by the abbreviation of the oxyalkyl group on the phosphorus head, and by the alkyl on the nitrogen atom - e.g. VX is designated as Et-iPr (modified from B11, B14 and P3).

The pX a (6.5-8.2) and nucleophilicity of MINA, 44, and of a series of aliphatic oximes derived from it, were found to be consistent with their ability to reactivate AChE inhibited by the nerve agents, sarin and VX. Yet, despite their ability to significantly reactivate AChE in the brains of sarin-intoxicated rats, these aliphatic oximes are not used as antidotes for treatment of OP poisoning in humans this is presumably due to their poor stability in aqueous solution and to their rapid clearance from the circulation. 

Fig. 1. Occurrence of H3 receptors inhibiting release of acetylcholine, of amino acid and monoamine neurotransmitters in the mammalian CNS in vitro. The schematic drawing represents a midsagittal section of the human brain three areas with a more lateral position are shown by broken line (substantia nigra and part of the hippocampus and of the striatum). For each of the six regions of the CNS (subregions given in brackets), in which H3 heteroreceptors have been identified, the neurotransmitter(s) and the species are indicated. The superscripts refer to the numbers of the papers as listed under References. Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig cerebral cortex. Note that a presynaptic location has not been verified for each of the H3 heteroreceptors or has been even excluded (for details, see Table 1). Abbreviations ACh, acetylcholine DA, dopamine GABA, y-aminobutyric acid Glu, glutamate 5-HT, 5-hydroxytryptamine, serotonin NA, noradrenaline...

The inhibition in brain AChE activity is the crucial facet of the neuroloxic effects of anti-ChEs in rodents and other test species, but such a measurement is obviously impossible to make in human subjects and indirect mcthod.s must be utilized. The inhibition in scrum or plasma ChE activity is often used as a index of potential inhibition in brain AChE activity in humans who may be exposed to anti-ChE. In the rat exposed to DFP. a significant hypothermic response was associated with an inhibition in serum ChE activity of 54% (Gordon and Fogelson, 1993), With other OPs, plasma or scrum ChE activity can plummet to below 25% of normal before there is a significant hypothermic effect. A 5-min exposure to vapors of DFP in the mouse causes core temperature to decrease by mure than 4 C within 30 min and remains depressed for approximately 4 hr (Scimeca et al., 1985). This was associated with a 66% inhibition in brain AChE activity that remained depressed despite a full recovery in core temperature and motor coordination. 

Galanthamine was reported to exert 50-fold selectivity against AChE than BChE by in vitro and in vivo experiments [28] and shown to inhibit AChE activity in human brain 10-fold less potent than that in human erythrocytes [34]. The pharmacokinetic data obtained from human subjects revealed that application of galanthamine hydrobromide at doses of 5 and 10 mg caused first-order pharmacokinetics, complete oral bioavailabihty, and a mean terminal half-life of 5.68 h [35]. 

MMB-4 was also less effective in reactivation of cyclosarin-inhibited rat brain AChE and sarin-inhibited human or monkey AChE compared with HI-6 (Kuca and Patocka, 2004 Lundy et al., 2011). MMBM was found to be a weak reactivator of tabun-inhibited human AChE (Worek et al., 2004). However, experimental data indicate that MMB-4 was superior to PAM-2 in reactivating OP-inhibited AChE and in preventing lethality in OP-poisoned animals (Worek et al., 2010). It was also reported that MMB-4 was the most effective oxime in reactivation of ChE in blood and peripheral tissues in guinea pigs poisoned by sarin, cyclosarin, VX, and VR (Shih et al., 2010). In addition, MMB-4 was reported to be a better AChE reactivator than PAM-2 in paraoxon-poisoned and methylparaoxon-poisoned rats (Petroianu et al., 2006,2007). 

To date, little postmortem work has been done in human cannabis abusers. Preclinical studies indicate that chronic treatment with 5 -THC markedly reduces CBj receptor binding in all brain areas containing this receptor (cerebellum, hippocampus, cortex, globus pal-lidus, striatum), and enhances the cAMP pathway (Rubino et ah, 2000). Other preclinical work has shown that the cannabinoid receptor reserve is larger than that for most other G protein-coupled receptor systems (Gifford et ah, 1999). This means that at occupancies as low as 0.13%, 50% of maximal inhibition of Ach release is achieved. 

Therapeutic application of AChE inhibitors requires the need to monitor the activity of this enzyme on the periphery. Since the brain is the target organ for all potential cholinergic drugs, any peripheral measures can provide important information about a compound efficacy and mechanism of action. Such studies are relatively non-invasive and simple. The reliable correlation between peripheral and central cholinesterase inhibition in humans depend on many factors, clearly vary from drug to drug, and require detailed pharmacokinetic studies. 

While 20 jimol L-1 A1C13 increased the AChE activity in RBC in all groups of investigated subjects to 158-285%, in the presence of 1 mmol L-1 NaF aluminum inhibited the AChE activity in intact RBC as well as in hemolyzate in all groups of investigated subjects (Table 1). The inhibition induced by AlFx was dependent on the concentration of fluoride in the cuvette (Fig. 2). The activation of AChE activity by 3.7 jimol L-1 Al3+ in the human RBC membranes and by 1-100 pmol L-1 Al3+ in bovine brain was observed by Zatta et al. [46],... 

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