Noncholinergic effects

One of the major mechanisms known for sarin-induced toxicity is the irreversible inhibition of the enzyme acetyl-eholinesterase (AChE), resulting in central accumulation of acetylcholine (ACh) and overexcitation of cholinergic neurons in sarin exposure related neurotoxicity. Besides this, a range of noncholinergic effects have been observed... 

ACh mediated excitation after stress. However, prolonged elevation in AChE-R, for example, following stress and anti-ChE intoxication, may damage cholinergic signaling and exert noncholinergic effects. 

Somani and Husain described the low-dose toxicity of tabun, sarin, soman, and VX under normal as well as stressful conditions. These authors explained the interaction of enviromnental and physical stress on cholinergic as well as noncholinergic effects induced by low-dose exposure to nerve agents and their potential for additive or synergistic neuropathologic sequelae. Under certain conditions, nerve agents may... 

Corbier, A., Robineau, R, 1989. Evidence for a direct noncholinergic effect of an organophosphorous compound on guinea-pig papillary muscles are ventricular arrhythmias related to a Na /K ATPase inhibition Arch. Int. 

NONCHOLINERGIC EFFECTS OF DFP IN REGENERATING HUMAN SKELETAL MUSCLE ... 

Gupta RC, Goad JT, Milatovic D, et al. 2000. Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects. Hum Exp Toxicol 19 297-308. 

As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter. Some of the substances identified to date are listed in Table 6-1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals. 

In conclusion, as an AChEI, HA possesses different pharmacological actions other than hydrolysis of synaptic ACh. HA has direct actions on targets other than AChE. These noncholinergic roles of HA could also be important in AD treatment. The therapeutic effects of HA are probably based on a multitarget mechanism. 

These include the effects of nerve agents on y-amino-butyric acid neurons and cyclic nucleotides. In addition, changes in brain neurotransmitters, such as dopamine, serotonin, noradrenaline, as well as acetylcholine, following inhibition of brain cholinesterase activity, have been reported. These changes may be due in part to a compensatory mechanism in response to overstimulation of the cholinergic system or could result from direct action of nerve agent on the enzymes responsible for noncholinergic neurotransmission. 

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