Manganese Inhalation as a Parkinson Disease Model

The present study examines the effects of divalent and trivalent Manganese (Mn2+/Mn3+) mixture inhalation on mice to obtain a novel animal model of Parkinson disease (PD) inducing bilateral and progressive dopaminergic cell death, correlate those alterations with motor disturbances, and determine whether L-DOPA treatment improves the behavior, to ensure that the alterations are of dopaminergic origin. CD-1 male mice inhaled a mixture of Manganese chloride and Manganese acetate, one hour twice a week for five months. Before Mn exposure, animals were trained to perform motor function tests and were evaluated each week after the exposure. By the end of Mn exposure, 10 mice were orally treated with 7.5 mg/kg L-DOPA. After 5 months of Mn mixture inhalation, striatal dopamine content decreased 71%, the SNc showed important reduction in the number of TH-immunopositive neurons, mice developed akinesia, postural instability, and action tremor; these motor alterations were reverted with L-DOPA treatment. Our data provide evidence that Mn2+/Mn3+ mixture inhalation produces similar morphological, neurochemical, and behavioral alterations to those observed in PD providing a useful experimental model for the study of this neurodegenerative disease

Effect of Chronic L-Dopa or Melatonin Treatments after Dopamine Deafferentation in Rats: Dyskinesia, Motor Performance, and Cytological Analysis

The present study examines the ability of melatonin to protect striatal dopaminergic loss induced by 6-OHDA in a rat model of Parkinson's disease, comparing the results with L-DOPA-treated rats. The drugs were administered orally daily for a month, their therapeutic or dyskinetic effects were assessed by means of abnormal involuntary movements (AIMs) and stepping ability. At the cellular level, the response was evaluated using tyrosine hydroxylase immunoreactivity and striatal ultrastructural changes to compare between L-DOPA-induced AIMs and Melatonin-treated rats. Our findings demonstrated that chronic oral administration of Melatonin improved the alterations caused by the neurotoxin 6-OHDA. Melatonin-treated animals perform better in the motor tasks and had no dyskinetic alterations compared to L-DOPA-treated group. At the cellular level, we found that Melatonin-treated rats showed more TH-positive neurons and their striatal ultrastructure was well preserved. Thus, Melatonin is a useful treatment to delay the cellular and behavioral alterations observed in Parkinson's disease

Manganese Inhalation Induces Dopaminergic Cell Loss: Relevance to Parkinson’s Disease

Parkinson’s disease (PD) experimental models are crucial in the assessment of possible therapies. Nevertheless, even though PD was one of the first neurodegenerative conditions to be modeled, there are limitations such as spontaneous recovery; lack of bilateral damage, which is a PD characteristic; animal intensive care after neurotoxin administration; and ultrastructural and biochemical nonspecific alterations but mostly the neurodegenerative time course observed in humans. In this chapter, we investigated the effects of divalent and trivalent manganese inhalation on rats and mice to obtain a novel PD animal model inducing bilateral and progressive dopaminergic cell death. We found that after 5 or 6 months of inhalation, there was more than 70% decrease in the number of TH-immunopositive neurons, and these alterations are correlated with an evident motor performance deficits manifested as akinesia, postural instability, and action tremor. More interesting is the fact that these alterations were reverted with l-DOPA treatment, implying that the motor alterations are associated with nigrostriatal dopaminergic innervation, postulating new light for the understanding of manganese neurotoxicity as an appropriate PD experimental model. Our results are contributing to the development of a suitable PD animal model, reproducible, sensitive, time-efficient, and readily applicable behavioral tests

Alzheimer-Like Cell Alterations after Vanadium Pentoxide Inhalation

Vanadium (V), a widely distributed transition metal, has been considered toxic, which depends on the valence of the compound. V pentoxide (V2O5) is considered the most harmful. Its long-term exposure produces neurotoxicity. Mice exposed to inhaled V2O5 displayed less tubulin+ in testicular cells and dendritic spines loss, cell death, and CA1 neuropil modifications, considered as the result of V interaction with the cytoskeleton, which made us suppose that V2O5 inhalation could initiate CA1 cell alterations comparable to what happen in the brains of Alzheimer disease (AD) patients. This study intends to demonstrate pyramidal CA1 cytoskeletal changes in rats which inhaled V2O5. Twenty rats were exposed to V2O5 0.02 M one hour, three times a week for several months. Our findings showed that V2O5-exposed rats had cell death that reached 56,57% after six months; we also observed collapsed strong argyrophilic nuclei and characteristic flame-shaped somas in all V2O5-exposed animals hippocampus CA1 compared to controls. We also found somatodendritic deformations. Neurite’s cytoskeleton exhibited visible thickening and nodosities and prominent dendritic spine loss. Our results demonstrate that V2O5 induces AD-like cell death with evident cytoskeletal and synaptic alterations

Behavioral and Cytological Differences between Two Parkinson’s Disease Experimental Models

The knowledge about the biochemical and behavioral changes in humans with PD has allowed proposing animal models for its study; however, the results obtained so far have been heterogeneous. Recently, we established a novel PD model in rodents by manganese chloride (MnCl2) and manganese acetate (Mn (OAc)3) mixture inhalation. After inhaling, the rodents presented bilateral loss of SNc dopaminergic neurons. Later, we conclude that the alterations are of dopamine origin since L-DOPA reverted the alterations. After six months, SNc significantly reduced the number of cells, and striatal dopamine content decreased by 71%. The animals had postural instability, action tremor, and akinesia; these symptoms improved with L-DOPA, providing evidence that Mn mixture inhalation induces comparable alterations that those in PD patients. Thus, this study aimed to compare the alterations in two different PD experimental models: 6-OHDA unilateral lesion and Mn mixture inhalation through open field test, rotarod performance and the number of SNc dopaminergic neurons. The results show that the Mn-exposed animals have motor alterations and bilateral and progressive SNc neurons degeneration; in contrast, in the 6-OHDA model, the neuronal loss is unilateral and acute, demonstrating that the Mn exposure model better recreates the characteristics observed in PD patients

Melatonin Pretreatment Effect in a Parkinson Disease Experimental Model Induced by the Inhalation of Manganese in Mice

Parkinson disease (PD) is characterized by dopaminergic neuron loss of the substantia nigra compacta (SNc) and motor alterations. Here, we used the experimental model of inhalation of the mixture of manganese chloride (MnCl2) and manganese acetate Mn (OAc)3 for inducing PD. This model causes bilateral and progressive degeneration of the SNc dopaminergic neurons. Melatonin has antioxidant properties and it has been suggested that it contributes to the protective effect in neurodegenerative diseases. Therefore, we aimed to determine whether melatonin pretreatment protects against the Mn-induced alterations. Before Mn inhalation, three groups were trained for motor performance (1. control group, 2. Mn mixture exposed without pretreatment, and 3. melatonin-pretreated/Mn-exposed groups) for motor tests. The motor coordination was evaluated through the single-pellet reaching task and the beam-walking test. After five months, all the animals were sacrificed. Dendritic spines were counted in the striatum medium-sized spiny neurons and the number of TH-immunoreactive neurons in the SNc. Our findings show that the melatonin-pretreated animals had better motor coordination and less dendritic spines and TH immunoreactive neuron loss than the Mn-inhalation-only group. Therefore, melatonin pretreatment has a neuroprotective effect and could be considered an alternative treatment before the more severe PD symptoms appear