ReviewOrganophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies
Introduction
Organophosphate (OP) compounds are a group of highly toxic chemicals that have been used widely as pesticides and developed as chemical warfare nerve agents such as soman (GD), sarin (GB), tabun (GA), cyclosarin (GF) and VX. OPs can be efficiently absorbed by inhalation, ingestion, and skin penetration. OP poisoning resulting from accidental or intentional (e.g. suicides by intentional ingestion of pesticides) exposure to pesticides is one of the most common poisonings worldwide, which causes approximately one million cases of poisoning each year with several hundred thousand deaths, mostly in developing countries (Pandit et al., 2011, Yurumez et al., 2007). Clinical manifestations may vary among victims of OP poisoning, depending on the specific compound, the amount, route, and length of time of exposure, as well as the age and health status of the person exposed.
OPs disrupt the functioning of cholinergic nervous system by irreversibly inhibiting acetylcholinesterase (AChE), which is responsible for the hydrolysis (breakdown) of acetylcholine (ACh) in the synapse. The inhibition of AChE by OPs results in both the accumulation of ACh at synapses of the central and peripheral nervous systems and overstimulation of cholinergic receptors that exceeds normal physiological limits (Gallo and Lawryk, 1991). Acute, excessive stimulation of cholinergic receptors (primarily the muscarinic receptor, mAChR, in the brain) causes cholinergic neuronal excitotoxicity and dysfunction, which are largely responsible for the cholinergic crisis in the acute phase of the OP exposures (within minutes), and could subsequently cause secondary neuronal damage and chronic neuropsychiatric consequences (Wiener and Hoffman, 2004, Apland et al., 2010). During recent years the research on cholinergic effects of OPs in the brain has become more clinically oriented. Great attention has been paid especially to the involvement of cholinergic neuronal excitotoxicity and neurotransmission deficits in the pathophysiology of secondary neuronal damage, and long-term neuropsychiatric and neurological consequences following exposure to OPs (Nordberg et al., 1990, Petras, 1994, Carpentier et al., 2008).
Section snippets
Cholinergic neuronal excitotoxicity and dysfunction resulting from irreversible inhibition of AChE by OPs
AChE is an enzyme that terminates synaptic transmission by hydrolytic degradation of the ACh into the inactive products – choline and acetic acid, at neuromuscular junctions and central cholinergic nervous system. ACh is the first compound to be identified as a neurotransmitter in the central nervous system (CNS). Not all parts of CNS contain ACh; those areas that have high concentrations are the cortex, hypothalamus, amygdale, thalamus and anterior spinal roots. Anatomically, two major
Secondary neuronal damage triggered by cholinergic neuronal excitotoxicity and dysfunction
Secondary neuronal damage is an indirect consequence of the initial lesion and a major contributor to the ultimate neuronal cell death and neural loss in the injured brain. Much of the damage done to the brain does not typically occur at the time of initial lesion and does not result directly from the initial lesion itself. A cascade of progressive neural injury and neuronal cell death is triggered by the initial lesion and possibly continues in the hours, days, weeks or months following the
Secondary neuronal damage and long-term neuropsychiatric and neurological disorders
Considerable evidence from both animal and human studies suggests that the cholinergic nervous systems are important for learning, memory and cognition (Drachman and Leavitt, 1974, Flicker et al., 1983, Ridley et al., 1986). The influence of cholinergic transmission upon memory and cognition could reflect the higher density of cholinergic pathways within limbic and paralimbic areas. An analysis of regional variations in cholinergic innervations suggests that cortical cholinergic pathways may
Potential therapeutic strategies for victims of OP poisoning
OP-induced brain damage, to date, is an irreversible neuronal injury (Deshpande et al., 2010), because, no pharmacological treatment is currently available to prevent or block secondary damage processes (Scalea, 2005). However, secondary neuronal damage processes offer a potential therapeutic window of opportunity (Armin et al., 2006) in which progressive neural injury and neuronal cell death may be prevented and the extent of disability may be reduced during the first few hours (Marion, 2003)
Conclusions
Considerable laboratory evidence from animal studies have showed that progressive neuronal cell death, neural loss and axonal degeneration occurred after OP exposure in the cholinergic regions of the brain that are predominantly affected by toxicity of OPs. This delayed secondary neuronal damage could result from cholinergic neuronal excitotoxicity and dysfunction that are caused by OP-induced irreversible AChE inhibition in the brain. It may largely involve the development of persistent
Conflict of interest statement
The authors report no declarations of interest.
Acknowledgments
The author would like to thank Mr. Jeffrey A. Koenig and Mr. Haoxing Chen for their valuable assistance in the preparation of this manuscript.
References (155)
Pharmacology of memory: cholinergic–glutamatergic interactions
Curr Opin Neurobiol
(1995)- et al.
Cytokines and acute neurodegeneration
Nat Rev Neurosci
(2001) - et al.
Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage
Neurotoxicology
(2010) - et al.
Higher susceptibility of the ventral versus the dorsal hippocampus and the posteroventral versus anterodorsal amygdala to soman-induced neuropathology
Neurotoxicology
(2010) - et al.
Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century
Neurol Res
(2006) - et al.
Primary brain targets of nerve agents: the role of the amygdala in comparison to the hippocampus
Neurotoxicology
(2009) - et al.
Biochemical and behavioral effects of soman vapors in low concentrations
Inhal Toxicol
(2004) - et al.
Treatment of organophosphate intoxication using cholinesterase reactivators: facts and fiction
Mini Rev Med Chem
(2007) Soman-induced morphological changes: an overview in the non-human primate
J Appl Toxicol
(1993)- et al.
Review of current evidence for apoptosis after spinal cord injury
J Neurotrauma
(2000)