Manganese Overexposure: Unveiling its Neurotoxic Potential and Involvement in Pathogenesis of Parkinson's Disease

doi:10.21203/rs.3.rs-4709449/v1

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Manganese Overexposure: Unveiling its Neurotoxic Potential and Involvement in Pathogenesis of Parkinson's Disease

https://doi.org/10.21203/rs.3.rs-4709449/v1

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Currently, the globe is undergoing a modern era and down the line, increased availability of luxurious goods and convenience (pesticides, utensils and comfy clothes) are also potential downsides to consider. Woefully, the manufacturing process of various essential need metals and chemicals. One such is manganese, an element, ubiquitously present in fruits and vegetables. Research substantiates that excessive exposure to Mn is deleterious to health and potentially leads to life-threatening diseases. In this context, Parkinson’s disease, is an insidious neurodegenerative disorder characterized by loss of dopaminergic neurones. The exact pathological culprit is still unknown and oxidative stress and inflammation are perceived to be the major delinquent. Overexposure to Mn disrupt various physiological process and cause inhibition of the ETC complex, mitochondrial failure, ROS generation, a-synuclein oligomerization, glutamate-mediated excitotoxicity and inflammation. In the present study, 28 days of intraperitoneal exposure to Mn ameliorate the motor coordination and grip strength confirmed by the strength glass chamber test and string test respectively. Moreover, the level of inflammatory marker and oxidative stress marker was also found to be increased. Cellular apoptosis was confirmed by estimating the caspase 3 level. Dopamine and glutamate levels were accessed by RP-HPLC in animal brain homogenate. The study comes to an end that overexposure to Mn is detrimental and cause neurotoxicity.

Manganese

Parkinson’s disease

Inflammation

Oxidative stress

Neurodegeneration

In order to make self-sufficient, people have to resort to a profession and are often exposed to a variety of harmful elements which on a chronic basis, affect the physiological function of humans. These elements interact with the biological process and disrupt homeostasis, resulting in various diseases. In this framework, Manganese (Mn) is transition metal, belonging to group 7 of the periodic table with atomic number 25. Manganese is a hard, greyish-white, brittle metal that is widely distributed in the Earth's crust [1]. Since Mn possesses significant industrial utility and is also essential dietary nutrient required in small amounts for the proper functioning of various physiological processes [2]. However, alongside its beneficial roles, potentially adverse effects are also downside to consider, and efforts should be made to minimize excessive environmental exposure to manganese.

Mn enter the human body primarily viz oral (dietary sources) and inhalation route (nasal mucosa, lining of lungs and gastrointestinal tract) by utilize tissue specific receptors or transporters such as transferrin (Tf R), divalent metal transporter 1(DMT1), ZIP, voltage gated calcium channel, glutamic acid ionotropic receptor (GLU R), choline and citrate transporters [2]. In the context of source of exposure, Mn serves various industrial purposes such as production of steel and iron [3]. It is also used as a component of firecrackers, welding, batteries, fertilizers, and ceramics [4]. In addition, Mn compounds are used as pigments in paints and as a catalyst in chemical reactions [5]. Besides, Mn has a potential physiological role and act as an essential nutrient required for the proper functioning of many enzymes in body. It is found in high concentrations in the brain, liver, pancreas, and kidneys [6]. Various endogenous enzymes such as lyases, pyruvate carboxylase, hydrolysis, glutamine synthase, isomerase and ligase use Mn as a co-factor for driven the physiological reactions. In addition, carbohydrates and cholesterol are also utilize Mn for their metabolism [2]. Despite its vitality, excessive exposure to Mn is detrimental and can contribute to pathogenesis of neurological problems, such as Parkinson's disease-like symptoms. Mn overexposure is reported to inhibit the ETC complex, mitochondrial failure, ROS generation, α-synuclein oligomerization, glutamate-mediated excitotoxicity and inflammation which are also similar with Parkinson’s Disease (PD) pathophysiology [2]. So, in the present study, we explore the neurotoxic effects of Mn exposure as compared to widely reported PD causing chemical rotenone.

PD is a chronic and progressive neurological disorder that affects movement. The disease is characterized by the loss of dopamine-producing neurons in the brain, which leads to several physical and cognitive symptoms. One of the most noticeable symptoms of PD is tremors, or involuntary shaking, bradykinesia, akinesia. Besides motor symptoms, cognitive changes, including memory, attention, and problem-solving abilities, are also common in PD [7]. Moreover, sleep disturbances such as insomnia or excessive daytime sleepiness, and mood changes, including depression and anxiety, can also occur in patients with PD [8]. PD is a complex disorder with multiple pathological factors involved. Several pathological factors such as accumulation of abnormal proteins (α-synuclein), mitochondrial damage, neurotransmitter imbalance, genetic alteration, inflammation and oxidative stress have been implicated in the development and progression of PD [9]. These triggering factors can damage dopaminergic neurons contributing to the neurodegeneration seen in PD. While the exact causes of PD are not fully understood, ongoing research is focused on identifying the underlying mechanisms of the disease and developing new treatments to slow or halt its progression.

Research credence that excessive exposure to Mn has been associated with an increased risk of developing PD due to the development of inflammation (via activating the NF-KB pathway) and oxidative stress (via inhibiting mitochondrial electron transporting chain complexes) in the brain [10,11]. In addition, Mn over-exposure has been shown to increase the accumulation of abnormal α-synuclein which is associated with the formation of Lewy bodies and the loss of dopamine-producing neurons in PD. It is thought that Mn may interfere with the normal degradation of α-synuclein and impair autophagy, which is a cellular process that is responsible for the degradation and recycling of damaged proteins, including α-synuclein [2]. These incite of Mn potentiate us to explore the Mn-associated molecular alteration and compare this alteration with rotenone, a well-known chemical used pre-clinically to develop PD. However, researchers have commonly used rotenone as an animal model to replicate important features of PD in experimental animals. Nevertheless, there have been concerns about issues such as high animal mortality rates, cost-effectiveness, and the safety of conducting these experiments. A study was found that 2–10 mg/kg intraperitoneal administration of rotenone exhibited a mortality rate exceeding 50% in animals within 30 minutes after administration [12]. Another study reported the mortality in two out of six animals after administering 3 mg/kg intraperitoneal rotenone [13]. Consequently, this study was conducted to examine whether Mn could be an alternative to rotenone in inducing PD-like effects in animals, with a specific emphasis on factors related to animal well-being and practical aspects of the research. The safety of Mn over rotenone is directly related to the LD-50 value of Mn which is more than rotenone. In the present study, we establish and validate a pre-clinical animal model for PD by administering MnCl₂ alone and in combination with rotenone and compared the PD-relevant effects of both the chemicals alone and in combination. The value of this Mn induced PD over rotenone is

2.1. Ethical approval

Experimental animals were obtained from the central animal house of ISF College of Pharmacy, Moga, India. The Institutional Animal Ethical Committee (IAEC) approved the experimental protocol (ISFCP/IAEC/CPCSEA/2021/Protocol no. 501/ meeting no. 30), and the experiments were conducted in compliance with CPCSEA guidelines for the ethical use and care of experimental animals.

2.2. Animal grouping

Male Wistar rats (180-230g) are randomly divided into 4 groups (7 rats in each) mentioned in TABLE 1. All the rats were housed in sterile polyacrylic cages in an animal house with air-conditioning having a temperature of 25 ± 3^oC, RH 55-60%, and a light/dark cycle for 12 hours. The water and food were supplied on an ad libitum basis. The behavioural parameters were performed between 9:00 and to17:00 hours.

2.3. Experimental protocol and treatment schedule

The study was conducted for 33 days including training days from 1^st to 5^th and the experimental protocol was for 28 days. The detailed experimental protocol is illustrated in Fig 1.

The saline, MnCl₂ and rotenone were administered to the respective group of animals for 28 days via the intraperitoneal route. The dose of MnCl₂ was 15mg/kg and rotenone was 1mg/kg. The combination group received both MnCl₂(15mg/kg) and rotenone (1mg/kg) for 28 days.

2.4. Chemicals and reagents

Rotenone and MnCl₂ were procured from (Sigma Aldrich, USA). ELISA kits for IL-6, and Caspase-3, were purchased from (Elabsciences, China). All the solutions used in the study were freshly prepared and were of analytical grade.

2.5. Parameters evaluated

2.5.1. Behavioural test

2.5.1.1. Strength glass chamber

This is a novel apparatus used to access the motor coordination and grip strength of rodents. This is a rectangular glass chamber and measures 40cm×40cm×80cm (LxBxH). There is a water outlet at the bottom, and a rod connected to the top has a curtain hanging from it for rats to climb from the bottom towards the rod. The rod is situated 2.5cm from the back wall, and the curtain is 44cm long and fixed 20cm above the bottom of the chamber. The time taken for the rat to climb from the bottom to the top is recorded, with a maximum time limit of 120 seconds.

2.5.1.2. String test

The String test apparatus is employed for evaluating the grip strength of rats. The apparatus comprises a slender steel wire measuring 2mm in diameter and 35cm in length. The apparatus is mounted at a height of 50cm above the ground, and the rat is positioned with its forepaws on the wire and allowed to hang. The time taken by the rat to hold onto the wire was noted in seconds. The latency time is an indirect measurement of the rat's grip or muscle strength when perched on the wire [14].

2.5.2. Biochemical tests

2.5.2.1. Estimation of Lactate Dehydrogenase (LDH)

LDH is a soluble enzyme found in the cytoplasm of the cell that defines the extent of cell damage. It is a marker of cellular oxidative stress. LDH level was estimated by using a commercial kit (coral clinical system). The brain was homogenized and centrifuged. The supernatant was taken and the LHD level was estimated as per the procedure given in the kit [15].

2.5.2.2. Estimation of Malondialdehyde (MDA)

MDA was quantified in brain homogenate using a spectrophotometric method, and the results were expressed in nmol/mg protein. To measure MDA, 0.2 ml of 8.1% SDS was mixed with 0.2 ml of tissue homogenate and 1.5 ml of a 20% solution of acetic acid. The resulting solution had a pH of 3.5. Next, 1.5 ml of a 0.8% aqueous solution of TBA was added, and the final volume was adjusted to 4.0 ml with distilled water. The solution was heated in a water bath at 95^oC for 60 minutes and then allowed to cool. After cooling, 1 ml of distilled water, 5.0 ml of n-butanol, and 15:1 (v/v) pyridine were added, and the mixture was shaken vigorously. The reaction solution was centrifuged at 4^oC for 10 minutes at 4000 rpm, and the amount of MDA was measured at 532 nm. All assay samples were run in triplicate [16].

2.5.3. Molecular markers and neurotransmitters

The molecular markers such as interleukin-6 (IL-6) [17] and Caspase-3 [18] were determined by using an ELISA kit as described manner in rat brain homogenate. The level of dopamine (DA) [19] and glutamate [20] was estimated by RP-HPLC-ECD as described in previous studies. BreezeTM 2 software was used to record and analyse the HPLC data.

2.6. Statistical analysis

The data were presented as mean ± SEM. The data from the behavioural analysis were analyzed by applying a two-way analysis of variance (ANOVA) and for multiple comparisons using the Bonferroni post hoc test. p˂0.05 was considered statistically significant. For biochemicals, molecular and neurotransmitters assessment, one-way analysis of variance (ANOVA) was applied and for multiple comparisons, Tukey’s post hoc test is used. p˂0.05 was considered statistically significant.

3.1. Behavioural parameters

3.1.1. Effect of rotenone and MnCl₂ in strength glass chamber test

This test was performed to assess the muscle's coordination. On the 7^th, 14^th and 21^st and 28^th day, the time taken by rats to climb upward on the strength glass chamber was significantly increased in rotenone alone and MnCl₂ alone treated animals as compared to the normal control (^#p < 0.05). Rotenone alone treated group took more time as compared to MnCl₂ alone group (^ap <0.05). Moreover, treatment with Rot + MnCl₂ showed a more significant elevation in latency time as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). Fig 2 represents the results as a graph.

3.1.2. Effect of rotenone and MnCl₂ in string test

This test was performed to assess the grip strength. On the 7^th, 14^th and 21^st, and 28^th day, the time taken by rats for holding the wire by forepaws was significantly decreased in rotenone alone and MnCl₂ alone treated animals as compared to the normal control (^#p < 0.05). The Rotenone group shows no significant difference as compared to MnCl₂ alone (^ap >0.05). Moreover, treatment with Rot + MnCl₂ shows a more significant reduction in latency time as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). Fig 3 represents the results as a graph.

3.2. Effect of rotenone and MnCl₂ in brain biochemicals (MDA and LDH)

Both MDA and LDH are the markers of cellular oxidative stress. We found that on day 29^th, the level of both the biochemicals was increased in rotenone alone and MnCl₂ alone treated animals as compared to the normal control (^#p < 0.05). Rotenone alone treated group showed more elevation in MDA and LDH levels as compared to MnCl₂ alone group (^ap < 0.05). Moreover, treatment with Rot + MnCl₂ showed a more significant increase in MDA and LDH levels as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). TABLE 2 represents the results.

3.3. Effect of Rotenone and MnCl₂ on IL-6

IL-6 is a marker of cellular inflammation. We found that on day 29^th the level of both the IL-6 and Caspase-3 was increased in rotenone alone and MnCl₂ alone treated animals as compared to the normal control (^#p < 0.05). Rotenone alone treated group showed more elevation in IL-6 and Caspase-3 levels as compared to MnCl₂ alone group (^ap<0.05). Moreover, treatment with Rotenone + MnCl₂ showed a significant increase in IL-6 and Caspase-3 levels as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). Fig 4 represents the results as a graph.

3.4. Effect of Rotenone and MnCl₂ on Caspase-3 level

Caspase-3 is a marker of apoptosis. We found that on day 29^th the level of Caspase-3 was increased in rotenone alone and MnCl₂ alone treated animals as compared to the normal control (^#p < 0.05). Rotenone alone treated group showed more elevation in Caspase-3 level as compared to MnCl₂ alone group (^ap <0.05). Moreover, treatment with Rotenone + MnCl₂ showed a significant increase in Caspase-3 level as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). Fig 5 represents the results as a graph.

3.5. Effect of Rotenone and MnCl₂ on DA and glutamate level

Rats administered with rotenone alone and MnCl₂ alone show a decreased level of DA and an elevated level of Glutamate as compared to the normal control on day 29^th (^#p < 0.05). Rotenone alone treated group had less level of DA and more level of glutamate as compared to the MnCl₂ alone group (^ap<0.05). Moreover, treatment with Rotenone + MnCl₂ shows a more significant decrease in DA and an increase in glutamate level as compared with normal control, rotenone alone, and MnCl₂ alone group (^*p < 0.05). Fig 6 represents the results as a graph.

This study examined the effect of Mn exposure on neurobiology and compare the PD-causing effect of Mn with rotenone. Various previous studies indicate that Mn exposure is toxic to neurons. It has been found that oxidative stress and inflammation are detrimental to neurons and may lead to neurological disorders such as PD. Research substantiates that chronic occupational or environmental exposure to Mn increases oxidative stress. By this, our findings show that 28 days i.p. exposure to Mn causes neurotoxicity by modulating the behavioural, biochemical and molecular markers. Mn administration reduces the motor activities of animals as confirmed via performing behavioural tests such as the strength glass chamber test and grip strength test. PD is a neurodegenerative disorder characterized by the progressive loss of dopamine-producing cells. Dopamine is a neurotransmitter responsible for the coordination of behaviour and movement of the body and the loss of dopamine leads to abnormal movements. In the present study, we were accessing the behavioural activity of animals on days 0, 7^th, 14^th, 21^st and 28^th and found a gradual reduction in motor coordination and grip strength of the animal. The animals administered with MnCl₂ show impairment in motor coordination and grip strength as compared to normal group animals shown in Fig 2 and 3. These results are from the previous study in which the PD-positive animal showed alteration in behavioural activities. However additional analysis reveals that Mn increases the level of MDA, LDH, IL-6 and Caspase-3. The previous study on rats shows that chronic MnCl₂ (20 mg/kg i.p.) exposure increased brain lipid peroxidation [21]. It has been reported that Mn interacts with the electron-transporting chain (ETC) and blocks the complexes of the ETC chain, thus increasing the oxidative stress inside neurons. Interestingly, blocked complexes cannot transfer the electron, resulting in the leakage of unpaired electrons, which raises the ROS level inside the cell. The rise in oxidative stress causes lipid peroxidation and therefore, the level of MDA has been increased [11]. The biochemical test for the detection of MDA confirms that Mn increases the MDA concentration in rat brain homogenate. Furthermore, the concentration of LDH, a marker of mitochondrial disruption, was increased on day 29^th. LDH level has been reported to increase in the condition when the mitochondrial respiratory chain is disrupted and respiration is shifted to anaerobic respiration. A publication insights that Mn enters the neurons Tf R and causes exocytosis of vesicles bound α-synuclein (a protein involved in the pathogenesis of PD). These vesicles then activate the nearly present microglia and induce the formation of pro-inflammatory cytokines [11]. By this, our study reveals that Mn administration increases the level of IL-6, a marker of inflammation Fig 4. The elevated level of IL-6 confirms that Mn plays a significant role in the induction of neuroinflammation and worsens neurotoxicity. In addition to this, the level of caspase-3 was also elevated in MnCl₂ treated group as compared to the normal group Fig 5. This may be due to the inhibition of ETC complexes by Mn. It has been reported that Mn inhibits the ETC complexes thus initiating the process of neuronal apoptosis. Due to ETC complex inhibition, the cytochrome-c is released from mitochondria and activates the caspases present in the cytoplasm, thus potentiating apoptosis [11]. The increased level of Caspase-3 in our study concretes this statement. Moreover, the imbalance in brain neurotransmitters also plays a curtailed role in various neurological disorders such as Alzheimer’s Disease (AD), PD, Depression, Autism and Amyotrophic Lateral Sclerosis (ALS) [22]. Our study shows that 28 days of administration of MnCl₂ causes alteration in neurotransmitter levels Fig 6. The DA which is essential for motor coordination was found to be decreased in rat brain homogenate. Furthermore, the concentration of glutamate, an excitatory neurotransmitter was found to be increased on day 29^th confirmed by HPLC. However, it is also worth noting that Mn is an essential nutrient that is required in small amounts for normal body functioning. A Mn deficiency can also lead to neurological problems but its detrimental effects associated with overexposure are also potential downside to consider. Therefore, it is important to maintain a balance of Mn in the body and avoid excessive exposure to this metal. Moreover, Mn can be a potential alternative to fatal chemical rotenone with lesser mortality rate and cause similar neurotoxicity.

This study investigated the potential of Mn as an alternative to rotenone in inducing PD in laboratory animals. To further advance our understanding of the pathogenesis of PD and the potential of Mn as an alternative model, future research should focus on elucidating the underlying mechanistic details. This entails a comprehensive exploration of the molecular pathways and cellular processes involved in Mn-induced neurotoxicity and their direct comparisons with those seen in the rotenone model. A deeper molecular understanding may unveil novel targets for therapeutic interventions and provide insights into the intricate nature of PD development. Optimizing the safety profile and dosage parameters for Mn exposure is of paramount importance. Future investigations should strive to pinpoint the precise dosage and duration of Mn administration that reliably induces PD-like symptoms while minimizing adverse effects. This fine-tuning of the Mn-induced PD model will enhance its reproducibility, consistency, and applicability in pre-clinical studies, ultimately facilitating more precise research outcomes. While the present study demonstrates Mn as a potential alternative to rotenone, ongoing research should seek to identify and characterize additional models that strike a balance between experimental practicality, ethical considerations, and physiological relevance. Diverse models can offer unique insights into different aspects of PD pathophysiology, broadening the scope of pre-clinical research. Utilizing the Mn-induced PD model, future research can focus on evaluating the efficacy of therapeutic interventions. Investigating neuroprotective agents, disease-modifying strategies, or symptomatic treatments within this model framework holds significant translational potential. Moreover, a comprehensive assessment of the long-term effects of Mn exposure is essential. Investigating the sustained neurodegenerative processes and behavioural changes over extended periods will provide valuable insights into the chronic aspects of PD. These avenues of investigation will collectively contribute to advancing our knowledge of PD and the development of more effective treatments for this debilitating neurodegenerative disorder.

DA, Dopamine; Divalent Metal Transporter 1, (DMT1); ETC, Electron Transporting Chain; Glutamic acid ionotropic Receptor, GLU R; IL, Interleukins; LDH, Lactate Dehydrogenase; MDA, Malondialdehyde; Mn, Manganese; PD, Parkinson Disease; Tf R, Transferrin Receptor; Zrt/Irt-like Proteins, ZIP;

Data availability: Data will be available on request by corresponding authors.

Funding: None

Acknowledgments: None

Conflict of interest: The authors declare that they have no financial or other conflicts of interest.

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TABLE 1: Animal grouping

S. No.	Groups	Animal Species	No. of animals
1.	Control group	Wistar rats	07
2.	Rotenone (1mg/kg i.p.) alone group		07
3.	MnCl₂(15mg/kg i.p.) alone group		07
4.	Rotenone(1mg/kg i.p.) + MnCl2(15mg/kg i.p.) group		07
	Total animals		28

TABLE 2: Effect of MnCl2 and rotenone on biochemicals

Experimental groups	MDA (nmol/mg pr)	LDH (U/L)
Normal control	1.604 ± 0.129	195.857 ± 6.905
Rotenone alone	7.641 ± 0.082^#a	369.428 ± 15.670^#a
MnCl₂ alone	6.647± 0.100^#	359.571± 5.735^#
Rot + MnCl₂	8.617 ± 0.104*	449.714 ± 6.479*

No competing interests reported.

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Manganese Overexposure: Unveiling its Neurotoxic Potential and Involvement in Pathogenesis of Parkinson's Disease

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1. Introduction

2. Material and methods

3. Results

4. Discussion

5. Conclusion and future indications

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