Enzyme inhibition in the central nervous system

The direct injection of sarin into the pons and medulla of the rabbit produces tachypnoea, bradycardia, hypotension and respiratory arrest which are reversed by the intravenous administration of atropine [73]. Respiratory arrest also is produced when sarin is injected into the lateral reticular nuclei of the rabbit and bradycardia occurs following its introduction into the ventrolateral reticular formation, an effect which may be reversed by both atropine and vagotomy [73], This suggests these to be the target sites in the brain of the rabbit at which cholinesterase inhibition results in respiratory arrest and bradycardia. 

Death due to cholinesterase inhibitors has been shown to be independent of the degree of inhibition of brain enzyme [51]. Maximum inhibition occurs within 24 hours of intoxication of rats with DFP, parathion, TEPP, schradan, E838 and EPN, but the rate of recovery differs for each compound [51]. Nevertheless, it has been claimed that death due to DF P occurs only when a critical level is reached in some organs, including the brain, of mice [74]. 

When brain cholinesterase is inhibited, the concentration of free acetylcholine rises. Symptoms of intoxication (for example fasciculations) are 

The injection of TEPP and a quaternary ammonium organophosphate, PPS (3-di-isopropoxyphosphinyloxy-A -methylpyridinium methylsulphate), into dogs results in 50 per cent inhibition of brain enzyme by the former and only 16 per cent by the latter [79]. Following injection of PPS directly into the lateral ventricle and subarachnoid space, cholinesterase inhibition is pronounced only in the immediate area of injection [79]. Studies on the acid oxalate and the quaternary methiodide of 2-diethoxyphosphinyl thioethyl dimethylamine [80] in rabbits show that the intravenous LD50 dose of the methiodide produces no inhibition of brain cholinesterase, while the LD50 dose of the acid oxalate produces approximately 90 per cent inhibition of the brain enzyme activity. Intraventricular injection of the methiodide at 1/10 to 1/100 the intravenous LD50 dose, however, produces approximately 90 per cent brain enzyme inhibition. 

Inhibitors of cholinesterase not only may cross the blood-brain barrier, but also may increase the permeability of the structure to certain compounds, for example anaesthetics [81] and sulphanilamide [82]. However, no causal relationship exists between the brain cholinesterase activity and the blood-brain barrier permeability [82]. Whereas schradan does not inhibit brain cholinesterase on systemic injection [51], it facilitates the penetration of the blood-brain barrier by sulphanilamide [82]. 

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