In the past, most studies on DQ poisoning primarily focused on damage to organs such as the kidneys, liver, and lungs. However, in recent years, there has been a growing number of reports highlighting neurological damage resulting from DQ poisoning. This emerging issue has garnered increased attention within the scientific community. Although the precise mechanisms of DQ toxicity remain incompletely understood, its impact on the nervous system is multifaceted. Existing research indicates that DQ can generate numerous redox products through redox processes, exerting a potent toxic effect on central nervous cells and as a crucial factor contributing to nervous system damage.

Oxid ative Stress Induced by DQ

DQ, a nonselective bipyridine herbicide, exerts its detrimental effects on various tissues and organs primarily through the generation of copious amounts of ROS and RNS via redox reactions within cells, resulting in oxidative stress [26]. This oxidative stress subsequently leads to cellular dysfunction [27]. Due to DQ’s high redox potential, it possesses an enhanced capacity to induce oxidative damage [28].

Upon entering the body, DQ undergoes reduction facilitated by nicotinamide adenine dinucleotide phosphate (NADPH) and cytochrome P450 reductase (CPR). This reduction process, accompanied by electron transfer from NADPH, gives rise to NADP + and an exceedingly unstable DQ radical (DQ + ·). DQ + ·, in turn, donates electrons to molecular oxygen (O2), resulting in the formation of the superoxide radical (O2· −) and the restoration of DQ + · to its original state. The significant production of O2· − within this cycle prompts the generation of ROS, such as hydrogen peroxide (H2O2), either spontaneously or through superoxide dismutase (SOD) catalysis. Normally, H2O2 is converted into water via catalase (CAT) and glutathione peroxidase (GPX). However, when ROS levels exceed the body’s regulatory capacity, cellular protective mechanisms, encompassing nonenzymatic elements like glutathione (GSH), thioredoxin, selenium, and vitamins C and E, as well as antioxidant enzymes including SOD, GPX, GR, and CAT, become overwhelmed, resulting in oxidative stress [3, 17, 29, 30].

Notably, DQ + · and O2· − can liberate iron from ferritin by reducing iron ions (Fe3 +) into ferrous ions (Fe2 +). These Fe2 + ions serve as catalysts in the Fenton reaction and the Haber–Weiss reaction, facilitating the conversion of H2O2 into the more potent hydroxyl radical (OH·), which wreaks havoc on biomolecules [31] (see Fig. 2). The accumulation of ROS within cells leads to DNA damage, while an abundance of hydroxyl radicals targets cellular lipid membranes, protein structures, and other macromolecules, resulting in structural damage to cell membranes and overall cellular harm. Additionally, the substantial consumption of CPR and NADPH leads to impairment of the cellular respiratory chain [32].

Fig. 2

Role of DQ in inducing oxidative and nitrosative stress. DQ, diquat; ROS, reactive oxygen species; RNS, reactive nitrogen species; CRP, cytochrome P450 reductase; SOD, superoxide dismutase; NADPH, nicotinamide adenine dinucleotide phosphate; HMP, hexose monophosphate pathway; CAT, catalase; GPX, glutathione peroxidase; GSH, glutathione; GSSG, glutathione (oxidized); Gred, glutathione reductase; FR, Fenton reaction; HWR, Haber–Weiss reaction

Moreover, DQ induces hypoxia within the body, leading to the heightened production of nitric oxide (NO). Under the influence of nitric oxide synthase (NOS), ROS and NO interact to generate peroxynitrite (ONOO−), which falls under the category of RNS. Excessive RNS levels can induce nitrosative stress, causing oxidative damage to intracellular lipids, proteins, and DNA [33]. ROS and RNS constitute vital small-molecule mediators within the body, and their excessive production disrupts the body’s antioxidant defense systems, triggering a severe oxidative stress response [34] (see Fig. 2).

Autophagy: Maintaining Cellular Homeostasis

Autophagy is a highly regulated and evolutionarily conserved lysosome-mediated process responsible for protein degradation and organelle recycling [35]. In the central nervous system, autophagy plays a pivotal role in preserving the functional integrity of nerve tissue by acting as a cellular guardian against damage and ensuring cellular homeostasis by removing damaged or redundant organelles.

Within the autophagy pathway, the interplay of PTEN-induced putative kinase 1 (PINK1) and Parkin proteins is crucial in mitochondrial autophagy regulation. Studies have revealed that exposure of PC12 nerve cells to a DQ solution results in the inhibition of mitochondrial complex I activity by DQ, leading to changes in mitochondrial membrane potential [36]. This perturbation inhibits the entry of PINK1 into mitochondria, thereby triggering the accumulation of PINK1, which subsequently activates and recruits the Parkin protein [37]. Activated Parkin proteins facilitate the ubiquitination and degradation of mitochondrial outer membrane proteins [38, 39], ultimately culminating in the autophagic clearance of damaged mitochondria.

Furthermore, DQ’s excessive ROS can activate protein kinase C (PKC). Activated PKC phosphorylates protein IκB [40], leading to the dissociation of IκB from nuclear factor-kappa B (NF-κB), thereby activating NF-κB. NF-κB orchestrates the regulation of the pro-apoptotic factor P53, ultimately augmenting P53 expression in PC12 nerve cells and causing its accumulation within the cytoplasm and nucleus [41]. When stress-induced damage becomes irreparable, P53 translocates to the mitochondrial outer membrane, releasing mitochondrial pro-apoptotic genes Bax and Bak. Bax and Bak each contribute to the formation of mitochondrial permeability transition pores (mPTP), culminating in the release of cytochrome C and the exacerbation of mitochondrial dysfunction. Ultimately, this cascade leads to apoptosis in PC12 nerve cells [42] (see Fig. 3).

Fig. 3

Mechanisms of DQ-induced neurotoxicity and apoptosis in PC12 nerve cells. (1) When PC12 nerve cells are exposed to a DQ solution, DQ inhibits mitochondrial complex I activity, causing changes in mitochondrial membrane potential and inhibiting PINK1 introduction to mitochondria. The accumulation of PINK1 triggers the activation and recruitment of Parkin protein, promoting the ubiquitination and degradation of mitochondrial outer membrane proteins, ultimately leading to the autophagic clearance of damaged mitochondria. (2) Reactive oxygen species (ROS) activate protein kinase C (PKC), which, in turn, phosphorylates protein IκB, leading to the dissociation of IκB from NF-κB and the subsequent activation of NF-κB. NF-κB regulates the expression of the pro-apoptotic factor P53, enhancing its expression in PC12 nerve cells and causing its accumulation in the cytoplasm and nucleus. When stress-induced damage becomes irreversible, P53 translocates to the mitochondrial outer membrane, triggering the release of mitochondrial pro-apoptotic genes Bax and Bak. Bax and Bak can form mitochondrial permeability transition pores, releasing cytochrome C, exacerbating mitochondrial dysfunction, and ultimately resulting in the apoptosis of PC12 nerve cells. DQ, diquat; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species; PKC, protein kinase C; NF-κB, nuclear factor-kappa B

Additionally, Cartelli et al. observed that the absence of Parkin protein in mouse cells resulted in microtubule over acetylation, inhibiting mitochondrial migration and transport [43]. In mice with Parkin deficiency, alterations in mitochondrial morphology and mitochondrial DNA (mtDNA) levels were evident, ultimately leading to degeneration and motor dysfunction of dopamine (DA) neurons [44, 45]. Parkin protein exists in a physiologically inhibited state, with activation occurring upon phosphorylation at the Serine65 (S65) site on its N-terminal ubiquitin-like (Ubl) domain [46]. Activated Parkin protein further facilitates autophagic clearance of damaged mitochondria by promoting ubiquitination and degradation of mitochondrial outer membrane proteins [47].

In summary, cellular damage inflicted by DQ may disrupt the delicate equilibrium within the autophagy process, representing a critical balance between cellular protection and the cytotoxic effects of DQ-induced stress and cellular damage. Park et al. reported that DQ activates NF-κB and p53 pathways to contribute to autophagy induction. Moreover, MAPK inhibitors control DQ-induced apoptosis and autophagy through mTOR signaling [48]. Fiesel et al. demonstrated the presence of mitophagy in the brains of Parkinson’s disease (PD) patients [49]. Kin et al. reported that DQ, when cytotoxic, induces both chaperone-mediated autophagy (CMA) and macroautophagy in SH-SY5Y cells. The induction of autophagy modulates cytotoxicity by suppressing apoptosis in DQ-exposed cells. CMA is vital in the degradation of pathological α-synuclein and the reduction of apoptosis in a DQ-induced α-synucleinopathy model [50].

Nerve Cell Degeneration

Parkinson’s disease is a neurodegenerative condition characterized by a range of symptoms stemming from a reduction in the production of dopamine transmitters in the substantia nigra region of the midbrain, disrupting the equilibrium among neurons responsible for controlling movement. Key pathological features include Lewy bodies formation and the degeneration of dopamine-producing neurons [51]. In addition to genetic factors, there is mounting evidence suggesting that environmental factors also contribute to the onset and progression of Parkinson’s disease (PD). Epidemiological and toxicological investigations have pinpointed DQ as a major neurotoxic substance linked to the pathogenesis of PD [52,53,54]. In cases of acute DQ toxicity, it can exert severe toxic effects on the central nervous system, leading to symptoms resembling PD [55].

Numerous studies have demonstrated that DQ induces mitochondrial dysfunction and triggers an inflammatory cascade involving microglial activation by generating oxidative stress [16, 17, 56, 57]. These processes may be implicated in the degeneration of dopaminergic neurons within the substantia nigra. Lindquist et al. [58] injected 14C-labeled DQ into the abdominal cavity of temporal forest frogs and observed that performing whole-body autoradiography in mice revealed low and relatively uniform levels of radioactivity in brain tissue. Accumulation of DQ in neuromelanin could potentially result in lesions of pigmented nerve cells, contributing to the development of Parkinson’s disease.

In vitro studies conducted by Dafna et al. on primary midbrain cultures from Sprague–Dawley rats revealed that DQ-induced alterations in the morphology and quantity of dopaminergic neurons and reduced dopamine uptake [16]. Additionally, Singh et al. [54] explored the protective mechanism of standardized extracts of Bacopa monnieri against neurotoxicity induced by PQ and DQ. Their findings suggest that Bacopa monnieri may safeguard rat adrenal medulla pheochromoma differentiated cell line PC12 cells by modulating disrupted cellular redox pathways associated with PD, potentially offering therapeutic benefits in preventing Parkinson’s disease.

Neuronal Axonal Degeneration

Neurons play a crucial role in the nervous system, transmitting information to other neurons or tissues via synapses. Among the components of neurons, the axon, also referred to as a nerve fiber, is the elongated projection responsible for conveying information from the cell body to other neurons or cells. Axonal degeneration is a process associated with neurodegenerative diseases like motor neuron disease [59], Alzheimer’s disease [60], and Huntington’s disease [61].

Fischer and Glass [62] conducted research confirming that oxidative stress constitutes a significant mechanism leading to axonal degeneration. They cultured dorsal root ganglion (DRG) neurons with a knockout of the SOD1 gene and observed significant axonal degeneration within 48 to 72 h. Importantly, the addition of SOD1 at this stage prevented such degeneration, thus validating that antioxidant treatment can mitigate this degeneration. Their study also assessed the sensitivity of wild-type DRGs to increased superoxide levels induced by DQ. The results demonstrated a positive correlation between axonal degeneration and the dose of DQ, with SOD1 deficiency exacerbating DQ’s toxicity. This finding suggests that DRG axons are susceptible to damage mediated by oxidative stress. DQ elevates intracellular superoxide production through oxidative stress, leading to axonal degeneration and degeneration. These results are a foundation for further investigations into oxidative stress-mediated axonal degeneration.

Pontine Myelinolysis

Central pontine myelinolysis (CPM) is a demyelinating disorder most commonly associated with rapid correction of hyponatremia, although it can also be linked to alcoholism, malnutrition, and chronic liver disease [63,64,65]. In 2020, Xing et al. [20] reported a case of acute pontine demyelination in acute DQ poisoning, ruling out sodium-related demyelination. Currently, it is believed that CPM’s pathogenesis is tied to the swift correction of hyponatremia, resulting in an imbalance of water and electrolytes inside and outside brain cells, damage to the blood–brain barrier, and apoptosis and myelinolysis of glial cells within the central nervous system. However, the specific mechanism by which DQ leads to CPM remains unclear and may be related to oxidative stress following DQ poisoning, affecting the apoptosis of central nervous system glial cells. This hypothesis warrants further investigation.