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

Differences Between Intact and Ovariectomized Hemiparkinsonian Rats in Response to L-DOPA, Melatonin, and L-DOPA/Melatonin Coadministration on Motor Behavior and Cytological Alterations

Parkinson?s disease (PD) higher incidence has been observed in postmenopausal women compared to premenopausal women, suggesting estrogen neuroprotective effect. L-DOPA (LD) chronic treatment causes dyskinesia; evidences indicate that LD increases the preexisting oxidative stress condition. This study determines melatonin ability, alone or in combination with LD (LD/Mel) to protect dopaminergic loss induced by 6-OHDA in a rat PD model in ovariectomized (OVX) and intact (with ovaries (W/OV)) rats on motor behavior and cytological alterations, comparing with LD-only treated rats. LD/Mel-treated rats showed dyskinesia decrease (score 5–7.5) and had the best performance in the staircase test (five pellets) throughout all studies. The beam walking time was 20–35 s, showing good coordination (as control group (20–38 s)), dopaminergic cells increase of 22.8% (W/OV rats) and 27.2% (OVX rats) in the contralateral side as well as 100% conservation in the contralateral dendritic spines. Our results suggest that LD/Mel co-administration and estrogen presence result in an efficient treatment to reduce dyskinesia through the conservation of some dopaminergic cells, which imply a well-preserved neuropil of a less denervated striatum. We assume that these results are because of a synergistic effect between LD, melatonin and estrogens

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