Cognitive and anxiety-like impairments accompanied by serotonergic ultrastructural and immunohistochemical alterations in early stages of parkinsonism

Leal, Pollyana Caldeira; Bispo, José M.M.; Lins, Lucas Correia; Souza, Marina F.; Gois, Auderlan M.; Moore, Charles F.; Marchioro, Murilo; Ribeiro, Alessandra Mussi; Silva, Regina H.; Meshul, Charles K.; Santos, José R.

doi:10.1016/j.brainresbull.2019.01.009

Cited by 11 publications

(5 citation statements)

References 77 publications

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“…It should be noted that the reserpine-induced reduction in TH could be related to a feedback inhibition of TH expression in DA neurons. In this respect, besides TH decrement in the nigrostriatal pathway, reserpine also causes increase in oxidative stress parameters ( Fernandes et al, 2012 ; Silva-Martins et al, 2021 ), increase in alpha-synuclein expression ( Leão et al, 2017 ), alterations in axonal ultrastructure ( Leal et al, 2019 ) and increase of neuroinflammation parameters (unpublished data). However, despite the several indicators that repeated reserpine induces some extent of neuronal damage compatible with Parkinson’s disease, it is important to mention that the TH decrement was partially recovered after prolonged withdrawal (in male rats— Santos et al, 2013 ).…”

Section: Discussionmentioning

confidence: 90%

“…Regarding non-motor alterations, which often appear before motor symptoms, cognitive deficits are highly prevalent in PD ( Roheger et al, 2018 ). The progressive parkinsonism induced by low dose-reserpine is a valuable tool that enables the evaluation of non-motor impairment, including emotional and cognitive deficits, during early stages of parkinsonism development in rodents ( Santos et al, 2013 ; Campelo et al, 2017 ; Leal et al, 2019 ). In a prior study, Santos et al (2013) reported impaired short-term object recognition memory before motor deficits in male rats (48 h after the 4th injection of reserpine).…”

Section: Discussionmentioning

confidence: 99%

“…The repeated low-dose reserpine protocol has been used as a model of progressive parkinsonism, showing phenomenological (progressive motor alterations) and construct (reduced dopaminergic parameters, increased oxidative stress, and augmented alpha-synuclein expression) similarities with PD ( Fernandes et al, 2012 ; Santos et al, 2013 ; Leão et al, 2015 , 2017 , 2021 ; Ikram and Haleem, 2019 ). Unlike neurotoxin models, which lead to acute severe motor impairment, the low-dose repeated reserpine protocol allows the observation of progressive motor impairments as well as premotor deficits such as cognitive prejudice, anxiety and nociception alterations ( Santos et al, 2013 ; Leal et al, 2019 ; Cintra et al, 2021 ; Dos Santos et al, 2021 ). This is of relevance when studying PD sex differences because women seem to have a later onset of the motor symptoms, while non-motor prodromic features are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson’s Disease

Lima

Meurer

Bioni

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. The main symptoms are motor signs such as resting tremor and difficulty in initializing movements. Non-motor alterations, such as cognitive deficits, can precede the motor symptoms. PD is more frequent in men than women. The mechanisms related to this difference are not completely understood. There is evidence that females present distinct characteristics in dopaminergic function compared to males. While the severity of motor impairments is often compared between sexes, little is known about sex differences in the prodromal stage. Most animal models of PD present acute severe motor impairment, which precludes the study of non-motor symptoms. Our research group have proposed an adaptation of the classic reserpine protocol, using low doses in a chronic treatment. This method allows the observation of progressive motor impairment as well as premotor deficits. Here we investigate possible behavioral and neuronal sex differences in the effects of the repeated treatment with a low dose of reserpine in rats. Male and female Wistar rats received 10–15 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. We followed-up the estrous cycle phases and conducted motor and cognitive assessments (catalepsy, open field, oral movements and object recognition tests). The euthanasia occurred 48 h after the 10th or 15th injections, with the collection of blood for the quantification of sex hormones and brains for tyrosine hydroxylase (TH) immunohistochemistry in the substantia nigra pars compact (SNpc). Reserpine induced progressive catalepsy, involuntary oral movements and cognitive deficits in male rats. The behavioral effects of reserpine were attenuated (motor) or absent (cognitive) in females. Reserpine decreased TH immunoreactivity in males, but not in females. Estrogen levels in females negatively correlated with catalepsy duration. Our findings show that females present a delay and/or a prevention in the reserpine-induced motor alterations in the progressive PD model, compatible with the lower prevalence of this disease in women. Further, females were protected from the deficit in object recognition at the prodromal stage. The absence of reserpine-induce decrease in TH immunoreactivity suggests that differences in dopaminergic function/plasticity are related to this protection in female sex.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson’s Disease

Lima

Meurer

Bioni

et al. 2021

Front. Aging Neurosci.

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“…Several pharmacological compounds, including reserpine, ibotenic acid, chlorpromazine, and haloperidol, have been used to induce reversible DA depletion ( Camacho-Abrego et al, 2014 ; Ogundele et al, 2015 ; Campêlo et al, 2017 ; Naeem et al, 2017 ). Reserpine exposure decreases brain monoamine storage capacity and total volume by inhibiting the vesicular monoamine transporter VMAT2, which models early-stage PD that progresses to PDD ( Ikram and Haleem, 2019 ; Leal et al, 2019 ). Reserpine-treated rodent models showed not only progressive catalepsy behavior and periods of oral twitching and reduced motor coordination but also developed impaired long- and short-term memory and learning ( Campêlo et al, 2017 ; Leal et al, 2019 ).…”

Section: Neurotoxin-induced Experimental Models Of Cognitive Impairmentmentioning

confidence: 99%

“…Reserpine exposure decreases brain monoamine storage capacity and total volume by inhibiting the vesicular monoamine transporter VMAT2, which models early-stage PD that progresses to PDD ( Ikram and Haleem, 2019 ; Leal et al, 2019 ). Reserpine-treated rodent models showed not only progressive catalepsy behavior and periods of oral twitching and reduced motor coordination but also developed impaired long- and short-term memory and learning ( Campêlo et al, 2017 ; Leal et al, 2019 ). Stereotactic injection of ibotenic acid into the subthalamic nucleus (STN) and pedunculopontine tegmental nucleus (PPT) can affect cholinergic neurons and the cholinergic system, thereby disturbing DAergic neurotransmission, which is associated with learning and memory ( Targa et al, 2018 ).…”

Section: Neurotoxin-induced Experimental Models Of Cognitive Impairmentmentioning

confidence: 99%

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Fan

Han

Zhao

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cognitive impairment is one of the key non-motor symptoms of PD, affecting both mortality and quality of life. However, there are few experimental studies on the pathology and treatments of PD with mild cognitive impairment (PD-MCI) and PD dementia (PDD) due to the lack of representative models. To identify new strategies for developing representative models, we systematically summarized previous studies on PD-MCI and PDD and compared differences between existing models and diseases. Our initial search identified 5432 articles, of which 738 were duplicates. A total of 227 articles met our inclusion criteria and were included in the analysis. Models fell into three categories based on model design: neurotoxin-induced, transgenic, and combined. Although the neurotoxin-induced experimental model was the most common type that was used during every time period, transgenic and combined experimental models have gained significant recent attention. Unfortunately, there remains a big gap between ideal and actual experimental models. While each model has its own disadvantages, there have been tremendous advances in the development of PD models of cognitive impairment, and almost every model can verify a hypothesis about PD-MCI or PDD. Finally, our proposed strategies for developing novel models are as follows: a set of plans that integrate symptoms, biochemistry, neuroimaging, and other objective indicators to judge and identify that the novel model plays a key role in new strategies for developing representative models; novel models should simulate different clinical features of PD-MCI or PDD; inducible α-Syn overexpression and SH-SY5Y-A53T cellular models are good candidate models of PD-MCI or PDD.

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Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism

Lopes-Silva,

Cunha,

Lima

et al. 2024

Exp Brain Res

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Cognitive and anxiety-like impairments accompanied by serotonergic ultrastructural and immunohistochemical alterations in early stages of parkinsonism

Cited by 11 publications

References 77 publications

Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson’s Disease

Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson’s Disease

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism

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