Neuroprotective Mechanisms Induced in Acute Organophosphate Poisoning

Amajad Iqbal, Kazi (2010) Neuroprotective Mechanisms Induced in Acute Organophosphate Poisoning. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.


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INTRODUCTION: Acute organophosphate poisoning During the first half of the nineteenth century an estimated 2-5 million cases of pesticide poisoning occurred world-wide of which 400,000 were fatal. WHO estimates around 3 million people are treated for the effects of organophosphate poisoning (OPP) with more than 200,000 deaths each year. OPP can occur in a variety of situations and can be accidental or suicidal. Acute OPP is a major cause of death in many middle and low-income countries where the problems associated with pesticide poisoning are significant. Studies from Asia have documented self-poisoning with pesticides as a predominant method of suicide. In Sri Lanka, China and Malaysia more than 60% of all suicides in rural areas are from organophosphate (OP) pesticide poisoning. OP pesticides are commonly consumed suicidal agents in Pakistan and South East Asia. Acute OPP is a major problem in South India. The incidence of self-harm with organophosphate pesticides is very high in young women in South India and accounts for 50-75% of all deaths. OP pesticides consumed in intentional self-harm are determined by their availability in different regions. The impulsive acts of self-harm in rural India to a largely extent reflect socioeconomically deprived households. Acute OPP is an important medical emergency in hospitals in India. OP compounds inhibit the enzyme acetylcholinesterase (AChE) and severe poisoning results in an autonomic cholinergic storm. However muscle weakness resulting from AChE inhibition is the major cause of morbidity in hospitalized patients. Although no specific treatment to reactivate AChE of poisoned patients is performed, patients who are intensively managed recover with minimal or no sequelae of poisoning. Recovery in the absence of specific treatment suggests activation of endogenous protective mechanisms, especially in the brain, the organ most sensitive to AChE inhibition due to its high density of cholinergic targets. AIM OF THE STUDY: The aim of the study was to determine neuroprotective mechanisms elicited in response to neurotoxic pathways induced by organophosphate pesticide poisoning in different regions of the brain. OBJECTIVES: Neuroprotection against OPP induced neurotoxicity was elucidated in different regions of the brain in rats by: 1. Determination of the expression and activity of brain AChE subsequent to acute severe OPP. 2. Study of the involvement of excitotoxic glutamatergic and inhibitory GABAergic systems in the brain subsequent to acute severe OPP. 3. Determination of oxidative stress, levels of antioxidant enzymes, neuroprotective antioxidant proteins heme oxygenase 1, metallothioneins I and III, cytoprotective HSP72 and neurotrophic factors (BDNF, NGF) in the brain in response to severe OPP. 4. Investigation of chronic sound stress preconditioning induced neuroprotection against acute severe OPP. This was by study of AChE activity and the glutamatergic/GABAergic systems in the brain following stress. MATERIALS AND METHODS: Acute monocrotophos poisoning and the activity and expression of brain AChE. This study explores a neuroprotective role for AChE in response to acute monocrotophos (MCP) poisoning in relation to enzyme expression, activity and kinetics. These properties of AChE were studied in cortex, striatum, hippocampus and cerebellum of rodents severely poisoned with MCP. The studies were carried out during recovery of rats from convulsions 2.5 hours after poisoning from convulsions, 24 hours after administration of MCP when rats had recovered from muscle weakness and 7 days, 14 days and 1 month later to evaluate complete recovery and CNS homeostasis. Monocrotophos Poisoning: Wistar rats (female 150-170 grams), maintained under standard laboratory conditions with free access to food and water were fasted for 12 hours and MCP (80% of LD50) in 1ml of distilled water was administered by oral gavage. This dose was selected in order to obtain acute severe central effects of OPP with visible signs of OP toxicity in the absence of animal death. All dosing was done between 8 am and 9 am. Rats were observed for cholinergic symptoms (salivation, lacrimation, body tremor and convulsions) and evaluated for muscle weakness, graded as 1) ataxic gait, 2) stretch movements only after stimulation of tails and 3) no voluntary movements even after stimulation of tails as given by De Bleecker [et al.]. Brains were removed immediately on sacrifice, rinsed with 0.9% NaCl and cortex, striatum, hippocampus and cerebellum dissected, snap frozen in liquid nitrogen and stored at -700C until use. Six animals were included in each group for statistical validity. The study was approved by the Institutional Review Board and Institutional Animal Ethics Committee of Christian Medical College, Vellore. RESULTS: Acetylcholinesterase activity in rat brain regions after acute MCP administration: In normal, control brains, AChE levels were highest in the striatum followed by the hippocampus, cortex and cerebellum. The levels were comparable in control cerebellum and cortex (Table 4.1.1). AChE was significantly inhibited in all brain regions, 56% in the cortex, 87% in the striatum, 68% in the hippocampus and 52% in cerebellum 2.5 hours after MCP administration. Regain in activity 24 hours after poisoning was 13% in the cortex, 33% in the striatum, 23% in the hippocampus and 25% cerebellum. AChE activity was not significantly inhibited in cortex and cerebellum 7 days after poisoning, while 40% inhibition was observed in the striatum and 21% in the hippocampus compared to controls. AChE activity returned to normal in all regions of the brain one month after poisoning. CONCLUSION: Chronic exposure to sound stress is neuroprotective in OPP. This is seen in an environment of high AChE inhibition resulting from increased MCP penetration into the CNS. The effectiveness of sound stress in protecting against OP induced neurotoxicity is through elevated GABA and increased uptake and breakdown of glutamate thus ensuring tolerance against MCP poisoning.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Acute Organophosphate Pesticide Poisoning, Brain acetylcholinesterase (AChE), excitatory glutamatergic, inhibitory GABAergic systems, Neuroprotective mechanisms.
Subjects: Respiratory Medicine > Neurology
> Respiratory Medicine > Neurology
Depositing User: Devi S
Date Deposited: 21 Jun 2017 07:36
Last Modified: 11 Sep 2022 04:46

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