Oxidative stress in the medullary respiratory neurons contributes to respiratory dysfunction in the 6-OHDA model of Parkinson's disease

Author(s):Show less -

Falquetto, Barbara ^[1] ; Thieme, Karina ^[2] ; Malta, Marilia B. ^[1] ; Rocha, Karina C. E. ^[1] ; Tuppy, Marina ^[1] ; Potje, Simone R. ^[3] ; Antoniali, Cristina ^[3] ; Rodrigues, Alice C. ^[1] ; Munhoz, Carolina D. ^[1] ; Moreira, Thiago S. ^[2] ; Takakura, Ana C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Inst Ciencias Biomed, 1524 Prof Lineu Prestes Ave, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Dept Physiol & Biophys, Inst Ciencias Biomed, BR-05508000 Sao Paulo, SP - Brazil

^[3] Sao Paulo State Univ UNESP, Dept Basic Sci, Sch Dent, BR-16015050 Aracatuba, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF PHYSIOLOGY-LONDON; v. 598, n. 22 SEP 2020.
• Web of Science Citations: 0

Abstract

Key points Parkinson's disease (PD) is associated with respiratory dysfunction. In the 6-OHDA rat model of PD this is seen as a reduction in respiratory frequency and minute ventilation during normoxia and hypercapnia stimulus. Respiratory dysfunction is caused by neuronal death of medullary respiratory nuclei in the 6-OHDA model of PD. Oxidative stress can be considered a strong candidate for neurodegeneration via miR-34c downregulation and pro-apoptotic signalling in respiratory neurons, preceding the functional impairment observed in the 6-OHDA model of PD. Parkinson's disease (PD) is a neurodegenerative disease caused by dopaminergic neuron death in the substantia nigra (SN). New evidence has revealed that this neurodegeneration is the result of complex interactions between genetic abnormalities, environmental toxins, mitochondrial dysfunction and disruption of the blood-brain barrier (BBB) in the SN. In addition to classic symptoms, PD patients also exhibit respiratory failure. Here, we investigated whether oxidative stress was associated with neurodegeneration in a respiratory group (RG) of 6-OHDA-treated rats, which act as a model of PD. We analysed how oxidative stress affected apoptotic signalling in the RG 30 days after 6-OHDA treatment, shortly before commencement of breathing impairment (40 days). After 30 days, a dihydroethidium assay showed increased oxidative stress in the RG, anti-apoptotic signalling, as shown by an increase in p-Akt and BcL-2 and a decrease in Bax in the caudal aspect of the nucleus of the solitary tract (cNTS), and a decrease in p-p38 and Bax levels in the retrotrapezoid nucleus (RTN); pro-apoptotic signalling was indicated by a decrease in p-Akt and BcL-2 and an increase in Bax in the rostral ventral respiratory group (rVRG) and pre-Botzinger complex (preBotC). miR-34c, a known oxidative stress protector, was downregulated in 6-OHDA animals in the RC. After 40 days of 6-OHDA, the NTS, rVRG, preBotC and RTN exhibited reduced NeuN immunoreactivity, no BBB disruption and an increase in thiobarbituric acid reactivity. We conclude that in the 6-OHDA model of PD, oxidative stress contributes to neurodegeneration in medullary respiratory neurons. (AU)

• FAPESP's process: 19/01236-4 - Effects of pharmacological and non-pharmacological treatments on respiratory changes observed in a murine model of Parkinson's disease
• Grantee: Ana Carolina Thomaz Takakura
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/05426-0 - MicroRNAs as metabolic mediators in the communication among white adipose tissue, liver and skeletal muscle in obese mice
• Grantee: Karina Cunha e Rocha
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/00065-1 - Oxidative stress in respiratory control of Parkinson Disease animal model
• Grantee: Bárbara Falquetto
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/07087-8 - The role of microRNAs in metabolic alterations promoted by diet-induced obesity or maternal obesity
• Grantee: Alice Cristina Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/03572-3 - The relationship between glucocorticoid receptor activation and the neuronal hyperexcitability in the basolateral amygdala in the restraint stress-induced long-lasting anxiety and their implications in the impaired contextual fear extinction
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/23376-1 - Retrotrapezoid nucleus, respiratory chemosensitivity and breathing automaticity
• Grantee: Thiago dos Santos Moreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/11268-0 - Mechanisms involved in medullary neurodegeneration in Parkinson's Disease
• Grantee: Bárbara Falquetto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral