Re: Malla BSSM, Kattamreddy AR. A case for banning paraquat in India: A public health concern. Natl Med J India. 2024;37:270–1

We read with interest the article by Malla et al. on the molecular mechanisms of paraquat toxicity and its environmental and health consequences.¹ We fully agree that the production and use of this herbicide should be banned worldwide, as it is potentially lethal if ingested in high concentrations.² As mentioned in the article by Malla et al., paraquat primarily exerts its toxic effects on the kidneys, liver, and lungs through increased oxidative stress, and also has a high potential for neurotoxicity.² Paraquat can cause not only Parkinson disease but also a variety of central nervous system impairments. These include epilepsy, Lewy body dementia, toxic encephalopathy, demyelinating diseases, incoordination, muscle weakness, confusion and coma.³

When paraquat is injected unilaterally directly into the substantia nigra of rats, it leads to increased motor activity, jumping and circling contralateral to the injection site.⁴ These clinical manifestations are associated with desynchronization of the electroencephalogram (EEG), epileptogenic high-voltage spikes and an increase in malondialdehyde levels.⁴ These behavioural, electroencephalogram and neuropathological effects can be prevented by injecting superoxide dismutase directly into the substantia nigra or intraperitoneally.⁴

Another mechanism for the neurotoxicity of paraquat is demyelination.⁵ Several studies have shown that paraquat has important effects on myelinating cells, the expression of myelin-related genes and myelin structure and it causes neuroinflammation, possibly contributing to demyelination.⁵

There is also evidence that paraquat disrupts the blood–brain barrier (BBB) and secondarily induces brain tissue damage by increasing interleukin-6 (IL-6) expression and oxidative stress through activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway.⁶ The use of PI3K inhibitors can attenuate paraquat-induced IL-6 overproduction, oxidative stress, BBB dysfunction and neuronal damage.⁶

There is also evidence that paraquat causes the accumulation of alpha-synuclein in neurons through the upregulation of histone deacetylase-6 (HDAC-6) and decreases the effective degradation of ubiquitinated alpha-synuclein by the HDAC-6-mediated aggresome-autophagy-lysosome pathway.⁷

In a study on paraquat-induced toxicity in mouse neural stem cells, it was shown that metabolic disturbances primarily affected the amino acid metabolic pathways of phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism.⁸ These disorders have been linked to oxidative stress, mitochondrial dysfunction and cell cycle dysregulation.⁸

In a study of C57BL/6 J mice treated with paraquat, it was found that paraquat interferes with KIF5A-mediated axonal mitochondrial transport in midbrain neurons.⁹ The administration of the MTNR1B receptor antagonist 4-P-PDOT could enhance the toxic effect.⁹ Reduced KIF5A expression, neuronal damage and motor deficits could be counteracted and alleviated by the administration of melatonin.⁹

Death in humans due to paraquat-induced convulsions¹⁰ could be prevented by the administration of activated charcoal, forced diuresis, haemofiltration, anti-seizure medications and the administration of antioxidants such as superoxide dismutase or astaxanthin.

In summary, we support the call by Malla et al.¹ for a ban on paraquat. Other methods of weed control (broad-leaved plants and grasses) in orchards and vineyards, as well as in coffee, tea, oil palm and banana plantations need to be invented and applied. Since paraquat is highly neurotoxic, physicians should be familiar with the management of acute and chronic paraquat intoxications.