Defying invisible threats…

Our goal : Protecting military and civil personnel with versatile, powerful antidotes against organophosphorus toxic agents and pesticides.

The Chemical Weapons Convention which prohibits the development, production, stockpiling, and use of chemical weapons worldwide came into effect in 1997. However, armed conflicts and terrorist attacks using such weapons remain a current threat. Recent examples of attacks attesting to the use of chemical weapons, particularly chemical warfare nerve agents (CWNAs), include the Syrian civil war with sarin in 2013 and 2017, the assassination of a North Korean man with VX at Kuala Lumpur airport in 2017 [3,4], but also the attempted assassinations with Novichok nerve agents of a former Russian spy and his daughter in Salisbury, United Kingdom, in 2018 and of a Russian government opponent in 2020.

NERVE GAS POISONING (Novichok, sarin, VX, pesticides…)

Mechanisms of toxic activity

Organophosphorus neurotoxic poisons primarily exert their effects by inhibiting acetylcholinesterase (AChE), an enzyme crucial for breaking down the neurotransmitter acetylcholine (ACh) in the synaptic cleft. Here’s a detailed look at their mechanism of action:

Inhibition of Acetylcholinesterase: Organophosphates bind to the serine residue in the active site of AChE, forming a stable complex. This prevents AChE from hydrolyzing ACh, leading to an accumulation of ACh at synaptic sites.
Excess Acetylcholine: The buildup of ACh results in prolonged stimulation of postsynaptic receptors, particularly at cholinergic synapses in the peripheral and central nervous systems.
Effects on the Nervous System:
- Muscarinic Receptors: Activation leads to symptoms such as salivation, lacrimation, urination, diarrhea, gastrointestinal distress, and bradycardia (SLUDGEM syndrome).
- Nicotinic Receptors: Overstimulation can cause muscle twitching, weakness, and ultimately paralysis due to continuous depolarization of the motor end plates.
Potential for Toxicity: High levels of ACh can lead to respiratory failure due to paralysis of the diaphragm and intercostal muscles, and can also affect central nervous system functions, leading to convulsions or coma.
Reactivation of Acetylcholinesterase: In some cases, the binding of organophosphates is irreversible aging, making the recovery of normal AChE activity very slow, which prolongs the toxic effects.

PESTICIDES

Epidemiology
Prevalence and Mortality: Pesticide poisoning is a leading cause of morbidity and mortality, particularly in developing countries. It is estimated that deliberate ingestion of pesticides results in over 168,000 deaths annually, accounting for about 20% of all suicides.
Types of Pesticides: Pesticides are generally categorized into household and agricultural types. Agricultural pesticides are more commonly involved in poisoning cases, especially in rural areas.

Geographical Distribution: The burden of pesticide poisoning is higher in developing countries. For instance, in rural China, pesticides account for over 60% of suicides, and similar high proportions are seen in rural areas of Sri Lanka, Trinidad, and Malaysia.

Underreporting: Non-fatal cases of pesticide poisoning are often underreported, which means the actual number of incidents is likely much higher than recorded.

Risk Factors: Key risk factors include easy access to pesticides, lack of proper storage, and insufficient regulation and enforcement. Additionally, socio-economic factors and mental health issues play significant roles.

Efforts to address pesticide poisoning include improving data collection, enhancing poison control centers, and implementing stricter regulations on pesticide use and storage.

PHYSIOPATHOLOGY

ACETYLCHOLINE, ITS PHYSIOLOGICAL ROLE

Acetylcholinesterase (AChE) plays a crucial role in the nervous system by breaking down the neurotransmitter acetylcholine (ACh) into choline and acetate. This process occurs primarily at neuromuscular junctions and cholinergic synapses, where it serves to terminate synaptic transmission.

Termination of Signal Transmission: AChE ensures that acetylcholine does not persist in the synaptic cleft, which would otherwise lead to continuous stimulation of muscles or neurons.
Regulation of Muscle Contraction: By breaking down acetylcholine, AChE helps regulate muscle contraction and relaxation. This is vital for normal muscle function and movement.
Prevention of Overstimulation: Without AChE, acetylcholine would accumulate, leading to excessive stimulation of muscles and neurons, which can cause conditions such as muscle spasms or even paralysis.

THE CHALLENGE OF REGENERATING ACETYLCHOLINESTERASE

Reactivating acetylcholinesterase (AChE) after poisoning, particularly with organophosphorus (OP) compounds like pesticides and nerve agents, presents several significant challenges:

Irreversible Inhibition: OP compounds inhibit AChE by phosphorylating the enzyme, leading to a stable and often irreversible bond. This makes reactivation difficult because the enzyme is effectively “locked” in an inactive state.
Aging Process: After inhibition, AChE undergoes a process called “aging,” where the phosphorylated enzyme undergoes further chemical changes, making it even more resistant to reactivation. The speed of aging varies with different OP compounds.

Limited Efficacy of Oximes: Oximes, such as pralidoxime (2-PAM), are the primary antidotes used to reactivate AChE. However, their effectiveness is limited and varies depending on the specific OP compound involved. Some oximes are not effective against certain nerve agents or pesticides.
Blood-Brain Barrier: Many oximes have difficulty crossing the blood-brain barrier, limiting their ability to reactivate AChE in the central nervous system. This is a critical issue because OP poisoning affects both peripheral and central cholinergic systems.
Side Effects and Toxicity: Oximes can have significant side effects and toxicity, which complicates their use. Finding a balance between effective reactivation and minimizing adverse effects is a major challenge.