Cholinergic system acetylcholinesterase activity

Catalpol. Zhang et al. [233] studied the neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the cholinergic system and inflammatory cytokines in the senescent mouse brain induced by D-galactose. Acetylcholinesterase (AChE) activity increased in senescent mouse brain and choline acetyltransferase (ChAT) decreased in the basal forebrain of senescent mouse. Muscarinic acetylcholine receptor Ml (mAChRl) expression declined and the levels of tumor necrosis factor (TNF-a), interleukin-ip (IL-ip), and advanced glycation end products... 

Acetylcholine Approximately 5% of brain neurons have receptors for ACh. Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best-characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer s disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). 

Generation of nitric oxide (NO) and evaluation of the central cholinergic system of male Sprague-Dawley rats after uranium exposure have also been studied (Abou-Donia et al., 2002). Intramuscular injection of 0.1 and l.Omg/kg for 7 days, followed by a 30-day observational period, resulted in sensorimotor deficits in rat behavior, differential levels of NO, and increased acetylcholinesterase activity in the cortex of animals dosed with 1 mg/ kg, suggesting multiple exposures to low doses of ura-nyl acetate caused prolonged neurobehavioral deficits in rats after the initial exposure has ceased, similar to the exposures of Gulf War veterans (Abou-Donia et al., 2002). 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

Nerve agents phosphorylate or phosphonylate the serine hydroxyl group at the esteratic part of the active site of the enzyme acetylcholinesterase (AChE EC 3.1.1.7) (Figure 66.2). AChE plays a key role in cholinergic transmission in the peripheral and central nervous system and, consequently, its inhibition is hfe-endangering (Taylor, 1996 Marrs, 1993). 

Cholinesterase inhibitors increase parasympathetic nervous system (cholinergic) activity indirectly by inhibiting acetylcholinesterase, thereby preventing the breakdown of acetylcholine. They are only effective in the presence of acetylcholine. They are listed in Table 1. 

Alzheimer s disease is associated with a progressive loss of cholinergic neurons in the brain that results in memory disturbances and cognitive dysfunction. One strategy for the treatment of Alzheimer s patients has been the use of acetylcholinesterase (AChE) inhibitors such as rivastigmine to enhance choUnergic activity in the central nervous system,... 

Early anatomical studies have employed acetylcholinesterase (AChE) histochemistry. However, AChE activity is disproportionally high in the cerebellum (reviewed in Silver, 1974), and its widespread distribution in non-cholinergic cells and fiber systems precludes its use as a marker for cholinergic neurons. 

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