【Neuro】Pesticides-induced Parkinson’s Disease

Pesticides-induced Parkinson’s Disease

Excess usage of insecticides leads to contamination of water source and soil. The toxicity of the pesticides may react to the environment and result in ecological disturbance and even species extinction. 

Pesticides taken in human body by drinking and food ingestion may act as the neurotoxin and carcinogens that affect humans’ health, especially the nervous system. 

Content:

1. The classification of insecticide
2. Mechanism of organophosphates & carbamates
3. Syndrome
4. Comparison between organophosphates & carbamates
5. Parkinson’s disease (PD) 
6. Reference

1. The classification of insecticide

There are four main chemical components under the classification of insecticide:

• Organophosphates (OPs)
• Carbamates
• Pyrethroids
• Organochlorine

Among all the others, OPs and carbamates are found to be the frequently used insecticides that contain compounds that may lead to Parkinson’s disease (PD). 

Organophosphates 

Organophosphates (OPs) also known as phosphate esters, are a class of organophosphorus compounds. General chemical structure of the organophosphate is O=P(OR)₃ , which is having a central phosphate molecule with alkyl or aromatic substituents. 

Example:

• Diazinon
• Chlorpyrifos
• Mipafox

Carbamate 

Carbamates are a class of insecticides structurally and mechanistically similar to organophosphate (OP) insecticides. Carbamates are N-methyl carbamates derived from a carbamic acid and cause carbamylation of acetylcholinesterase at neuronal synapses and neuromuscular junctions. 

subdivided into 

• Aldicarb 
• Carbaryl

2. Mechanism of organophosphates & carbamates

Organophosphate

• chiefly inhibit the enzyme acetylcholinesterase (AChE) that is mainly used to break down the neurotransmitter acetylcholine (ACh) found in the peripheral and central nervous system.
• lead to destructive effects on the central and peripheral nervous system.
• The inhibition of acetylcholinesterase may also lead to accumulation of acetylcholine at cholinergic synapses and causes cholinergic syndrome

Cholinergic syndrome

Syndromes of muscarinic cholinergic receptors hyperactivation:

• lacrimination
• pupil constriction
• bradycardia
• salivation
• emesis
• defecation
• gastrointestinal cramps

Syndromes of nicotinic cholinergic receptors hyperactivation:

• sweating
• pupil dilation
• bronchodilation
• tachycardia
• hypertension
• fasciculations
• bradykinesia

Carbamates

The mechanism of toxicity of carbamates is similar with OPs as it is also the inhibitor of AChE.

• But, carbamates inhibition is temporary and rapidly adjustable compared with OPs inhibition.
• Also, carbamylated AChE does not experience the aging reaction
• due to apid recurrence of the carbamylated enzyme

3. Syndrome

Organophosphate

First four days

• experience muscle weakness or even death if respiratory muscles are affected

After two to three weeks of exposure

• develop OP-induced delayed polyneuropathy (OPIDP), with symptoms of 
• sensory abnormalities
• muscle cramps
• weakness
• paraplegia
• these symptoms are the consequences of irreversible axonal death due to neuropathic OP compounds inhibit a neural enzyme called neuropathy target esterase.

Neuropathy target esterase 

• also known as patatin-like phospholipase domain-containing protein 6 (PNPLA6) 
• has serine esterase activity and can hydrolyze ester, peptide, and amino acid
• The active site of neuropathy target esterase, the nucleophilic serine residue
• attacks the carbonyl carbon atom of the substrate
• forming a covalent acyl-enzyme intermediate, which is subsequently hydrolyzed.
• the esterase activity of neuropathy target esterase is susceptible as covalent inhibition by organophosphates which forms an analogous phosphyl-enzyme intermediate. 
• The binding of organophosphates compounds and active serine site is irreversible and leading to OPIDP.

Carbamates

• The syndromes of exposure to carbamates are similar to organophosphates
• But, Duration is typically less than 24 hours and reversible
• Different from organophosphates, patients may develop syndrome within 5 minutes after massive exposures.
• Generally, acute intoxication of carbamates may resolve within few hours.
• This is because the instability of carbamylated serine residue and the separable structure of carbamyl moiety from enzyme by spontaneous hydrolysis.
• Subsequently, 90% of toxicity will renally excreted in several days.
• Besides, carbamates are not able to dealkylate, which mean aging the cholinesterase after inhibition.
• Hence, carbamates are not delayed neuropathy inducers and also unable to develop OPIDP.

4. Comparison between organophosphates & carbamates

Same: 

• possess similar poisoning mechanisms
• ultimately cause cholinergic syndrome
• which hyperactivate muscarinic cholinergic receptors and nicotinic cholinergic receptors.

Difference:

• OPs irreversibly bind to acetylcholinesterase whereas carbamates reversibly bind to the enzyme. 
• OPs experience the aging reaction while carbamates do not experience the aging reaction.

Insecticide class	Example	Mechanism	Syndrome
Organophosphates (OPs)	Diazinon Chlorpyrifos Mipafox	Inhibition of AChE	• Cholinergic syndrome • Slow responsive process • OP-induced delayed polyneuropathy (OPIDP) with syndrome of sensory abnormalities, muscle cramps, weakness and paraplegia
Carbamate	Aldicarb Carbaryl	Inhibition of AChE	• Cholinergic syndrome • Duration exposure to carbamate is typically less than 24 hours and reversible

5. Parkinson’s disease (PD) 

A well-known disease that caused by loss of dopaminergic neuron in the substantia nigra pars compacta which links to decrease in dopamine production. 

Dopaminergic neuron responsible to innervate the basal ganglia and associated to motor syndromes including rest tremor, rigidity, bradykinesia and loss of automatic movements in PD. 

a. A long-term exposure to organophosphates and carbamates causes the neurotoxin to further inhibit acetylcholinesterase. 

• Without AChE, ACh is unable to degrade. 
• Hence, it leads to the imbalance between cholinergic activity and dopaminergic activity. 
• This is the mechanism of occurrence of rest tremor and rigidity. 
• Rest tremor is referring to unintentional and uncontrollable rhythmic movement of any parts of the body when the muscle is relaxed. 

b. Damage to the dopaminergic neuron in substantia nigra pars compact 

• decrease the dopamine production
• inhibit the direct pathway but enhance the indirect pathway.
• Direct pathway express D1 receptors (D1R): increases intrinsic excitability 
• Indirect pathway express D2 receptors (D2R): decreases intrinsic excitability. 

Less dopamine secretion from substantia nigra compact impact on

i. Direct pathway

• less stimulatory input from D1R 
• the action potentials of GABAergic neuron decrease 
• As a result, it inhibits impulse transmission to cerebral cortex
• decreases neuromuscular transmission. 

ii. Indirect pathway

• less inhibitory input from D2R
• the action potentials of GABAergic neuron which located in subthalamic nucleus increase 
• release a lot of glutamate which is a stimulatory neurotransmitter. 
• Glutamate cause stimulation in internal globus pallidus 
• causing release a lot of gamma-aminobutyric acid (GABA). 
• Copious GABA will inhibit neuron within thalamus
• further inhibit the impulses that going to cerebral cortex
• so it will decrease neuromuscular transmission, 
• contributed to bradykinesia and loss of automatic movements
• Bradykinesia refers to the slowness of movement. 

c. Lewy bodies 

• abnormal aggregations of alpha-synuclein in substantia nigra and the locus coeruleus
• microscopic markers of PD
• The presence of Lewy bodies will cause significant cell loss
• lead to manifestation of non-motor symptoms, such as fatigue, hypotension.

6. Reference

Kamel, F., & Hoppin, J. A. (2004, June). Association of pesticide exposure with neurologic dysfunction and disease. Environmental health perspectives. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247187/.

Mayo Foundation for Medical Education and Research. (2020, December 8). Parkinson's disease. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055.

Neuropathy Target Esterase. Neuropathy Target Esterase - an overview | ScienceDirect Topics. (n.d.). https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/neuropathy-target-esterase.

Parkinson's Disease: Causes & Pathophysiology: Part 2. (2017). YouTube. https://youtu.be/rFoc4ACFehQ.

Pinto, D. (2018, August 17). Study Reveals Alpha-synuclein's Role in Parkinson's, Lewy Body... Parkinson's News Today. https://parkinsonsnewstoday.com/2018/08/14/alpha-synuclein-disrupts-protein-production-parkinsons-lewy-body-dementia/?cn-reloaded=1.

Silberman, J. (2021, May 12). Carbamate Toxicity. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK482183/.

Toxicology of Acetylcholinesterase Inhibitors (I) - Neurotransmission. (2017). YouTube. https://youtu.be/ReMecYLUa0s.

Zhai, S., Tanimura, A., Graves, S. M., Shen, W., & Surmeier, D. J. (2018, February). Striatal synapses, circuits, and Parkinson's disease. Current opinion in neurobiology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022405/. 

NEXT:

PREVIOUS:

【Pharmacology】Drugs for Parkinson’s disease