Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of Parkinsonism with severe neurodegeneration

doi:10.1016/j.neuroscience.2007.07.038

Neuroscience

Volume 149, Issue 1, 12 October 2007, Pages 28-37

https://doi.org/10.1016/j.neuroscience.2007.07.038 Get rights and content

Abstract

Physical rehabilitation with endurance exercise for patients with Parkinson’s disease has not been well established, although some clinical and laboratory reports suggest that exercise may produce a neuroprotective effect and restore dopaminergic and motor functions. In this study, we used a chronic mouse model of Parkinsonism, which was induced by injecting male C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) and probenecid (250 mg/kg) over 5 weeks. This chronic parkinsonian model displays a severe and persistent loss of nigrostriatal neurons, resulting in robust dopamine depletion and locomotor impairment in mice. Following the induction of Parkinsonism, these mice were able to sustain an exercise training program on a motorized rodent treadmill at a speed of 18 m/min, 0° of inclination, 40 min/day, 5 days/week for 4 weeks. At the end of exercise training, we examined and compared their cardiorespiratory capacity, behavior, and neurochemical changes with that of the probenecid-treated control and sedentary parkinsonian mice. The resting heart rate after 4 weeks of exercise in the chronic parkinsonian mice was significantly lower than the rate before exercise, whereas the resting heart rate at the beginning and 4 weeks afterward in the control or sedentary parkinsonian mice was unchanged. Exercised parkinsonian mice also recovered from elevated electrocardiogram R-wave amplitude that was detected in the parkinsonian mice without exercise for 4 weeks. The values of oxygen consumption, carbon dioxide production, and body heat generation in the exercised parkinsonian mice before and during the Bruce maximal exercise challenge test were all significantly lower than that of their sedentary counterparts. Furthermore, the exercised parkinsonian mice demonstrated a greater mass in the left ventricle of the heart and an increased level of citrate synthase activity in the skeletal muscles. The amphetamine-induced, dopamine release-dependent locomotor activity was markedly inhibited in the sedentary parkinsonian mice and was also inhibited in the exercised parkinsonian mice. Finally, neuronal recovery from the loss of nigrostriatal tyrosine hydroxylase expression and dopamine levels in the severe parkinsonian mice after exercise was not evident. Taken all together, these data suggest that 4 weeks of treadmill exercise promoted physical endurance, resulting in cardiorespiratory and metabolic adaptations in the chronic parkinsonian mice with severe neurodegeneration without demonstrating a restorative potential for the nigrostriatal dopaminergic function.

Section snippets

Animals

Ten to 12-week-old male C57BL/6 mice (Charles River Laboratories, Inc., Wilmington, MA, USA), weighing between 25 and 27 g at the beginning of the study, were housed in single cages with food pellets and water available ad libitum. The room was maintained at a constant temperature and humidity on a 12-h light/dark cycle. A total of 58 mice were used in the current study. All animal treatments were carried out strictly according to the National Institutes of Health Guide for the Care and Use of

Locomotor deficit and endurance exercise training

The spontaneous movement in chronic PK mice was recorded and compared with that of the probenecid-treated control mice. We detected a marginal change, although not a statistically significant increase, in the inconsistency of movement pattern (ApEn) in mice 1, 3, and 7 days after the last injection with MPTP/probenecid. Our analyses indicated no significant differences in the main effect for Group (F(1,4)=1.76, P=0.26) and for Day (F(2,8)=1.49, P=0.28). However, there was a significant

Discussion

Patients with PD are confronted with at least two impediments: one is the progressive degeneration of the nigrostriatal neurons and the other is the resulting physical impairments and disabilities. In order to alleviate neurodegeneration and improve motor performance and quality of life in PD patients, elucidation of neuroprotective and neurorestorative processes and examination of strategies steering toward physical rehabilitation are highly relevant.

According to a research synthesis, it is

Acknowledgments

The authors thank Ms. Christina Roels, Ms. Christiane Kodra, and Mr. Eric Cheng for their assistance in exercise training of the animals and in collecting behavioral measurements. We appreciate Dr. Karen Kuphal’s helpful suggestions to the manuscript. This study was supported by a grant from the National Institute of Neurological Disorders and Stroke (NS 47920). Preliminary results of this study were published in abstract form at the Annual Society for Neuroscience meeting in Atlanta, Georgia,

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Furthermore, amphetamine-induced locomotion, a stereotypic behavior that depends on DA receptors, was not rescued by endurance exercise (Al-Jarrah et al., 2007; Conti et al., 1997; Pothakos et al., 2009). Exercised PD mice had a slight but not statistically significant increase in Tyrosine Hydroxylase, the rate-limiting enzyme in DA synthesis (Al-Jarrah et al., 2007; Nagatsu, 1995). While differences in genetic background, MPD administration and sample size likely contribute to variability in results, it is striking that endurance exercise might restore function even in the absence of significant nigrostriatal restoration.
Endurance exercise is a widely accessible, low-cost intervention with a variety of benefits to multiple organ systems. Exercise improves multiple indices of physical performance and stimulates pronounced health benefits reducing a range of pathologies including metabolic, cardiovascular, and neurodegenerative disorders. Endurance exercise delays brain aging, preserves memory and cognition, and improves symptoms of neurodegenerative pathologies like Amyotrophic Lateral Sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and various ataxias. Potential mechanisms underlying the beneficial effects of exercise include neuronal survival and plasticity, neurogenesis, epigenetic modifications, angiogenesis, autophagy, and the synthesis and release of neurotrophins and cytokines. In this review, we discuss shared benefits and molecular pathways driving the protective effects of endurance exercise on various neurodegenerative diseases in animal models and in humans.
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In relation to non-motor behavior, studies described: improvement in memory analyzed by the water maze test (n = 3) (Aguiar et al., 2016a; Rezaee et al., 2019b; Viana et al., 2017), spatial memory (n = 1) (Shahidani et al., 2019), novel object recognition test (n = 1) (Real et al., 2019), passive avoidance test (n = 3) (Sung, 2015; Shahidani et al., 2019; Hamzehloei et al., 2019), and step-down avoidance task (n = 1) (Cho et al., 2013); reduced depressive behavior analyzed by the forced swimming test (n = 2) (Tuon et al., 2014; Shin et al., 2017b); decreased anxiety like behaviors in the elevated plus maze (n = 2) (Gorton et al., 2010; Dogru and Bal, 2019) and marble burying tests (n = 1) (Gorton et al., 2010); reduced disturbances in self-care behavior in the splash test (n = 1) Viana et al., 2017); and increased nociceptive threshold in the mechanical hyperalgesia test (n = 1)(Binda et al., 2020). On the other hand, some studies did not observe effects of exercise on some of the behavioral tests performed, such as the rotational test (n = 4) (Shi et al., 2019; Al-Jarrah et al., 2007; Landers et al., 2013; Landers et al., 2014); beam test (n = 1) (Wang et al., 2013); parallel rod activity chamber (n = 1) (Churchill et al., 2017); cylinder test (n = 1) (Binda et al., 2020); forelimb placement asymmetry test (n = 2) (Landers et al., 2013; Landers et al., 2014); and rearing test (n = 2) (Landers et al., 2013; Landers et al., 2014). This subsection describes other mechanisms and pathways that are not directly related to the nigrostriatal dopaminergic system.
Parkinson’s disease (PD) is a progressive disabling brain disorder. Physical exercise has been shown to alleviate the symptoms of PD and, consequently, improve patient quality of life. Exercise mechanisms involved in beneficial effects on PD have been widely investigated. This study aims to systematically review the literature on the use of treadmill exercise in PD animal models. The study was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Searches were conducted in MEDLINE, EMBASE, and ISI databases. In total, 78 studies were included. The dopaminergic system, behavior, neuroplasticity, neuroinflammation, mitochondria, and musculoskeletal systems were some of the outcomes evaluated by the selected studies. Based on the systematic review center for laboratory animal experimentation (SYRCLE) RoB tool, the methodologies revealed a high risk of bias and lack of information about study design, which needs attention for data reproducibility. This review can guide future studies that aim to fill existing gaps regarding the effects of treadmill exercise in PD animal models.
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A recent study from O'Dell et al. suggested that exercise could evoke the remaining DA cells to enhance their overall dopaminergic function (O’Dell et al., 2007). In addition, the remaining SN cells partially normalize striatal DA signaling through increased DA release in the 6-hydroxydopamine (6-OHDA) lesion models (Al-Jarrah et al., 2007). These supports our findings that MPTP + EX group had almost recovered dopamine level than MPTP group.
Treadmill exercise has been recognized as an effectively therapeutic strategy for Parkinson's disease (PD). However, its exact molecular mechanism of promoting PD remain unclear. Recently, the NLRP3 inflammasome is considered to play a critical role in the pathogenesis of PD. In this study, we investigated whether NLRP3 inflammasome was involved in treadmill exercise-induced neuroprotection and anti-inflammation effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. 8-week-old male mice (C57BL/6 strain) were divided into four groups: Control, MPTP, MPTP + EX and EX. MPTP was intraperitoneally injected into mice to establish chronic PD model. The open-field test and pole test were used to assess motor function. The results showed that treadmill exercise significantly alleviated motor dysfunction and dopaminergic neuron degeneration induced by MPTP. In addition, we also found that treadmill exercise suppressed MPTP-triggered microglia activation and the co-localization of NLRP3+/Iba-1+ cells in the substantia nigra. These effects were associated with suppression NLRP3 inflammasome via down-regulation of TLR4/MyD88/NF-κB pathway. Overall, our study demonstrated that treadmill exercise could effectively alleviates neuronal damage via inhibition of NLRP3 inflammasome and microglial activation in MPTP‐induced PD mouse model.
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Parkinson’s disease (PD) is caused by neurodegeneration of nigrostriatal neurons, resulting in dopamine (DA) stimulated motor deficits. Like brain derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (DHF) is an agonist of the tropomyosin receptor kinase-B (TrkB) and stimulates the same secondary cascades that promote neuronal growth, survival and differentiation. We used our progressive mouse model of PD by administering increasing doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks (5 days/week), and then treated mice with DHF for 4 weeks after the cessation of the toxin injections (i.e., restoration). Mice treated with DHF recovered motorically, even after MPTP administration. Despite a 75% loss of tyrosine hydroxylase (TH) expression in the dorsolateral (DL) striatum in the MPTP group, mice treated with DHF had a recovery comparable to that found in the respective control. There was no recovery of DA tissue levels within the DL striatum. In both the DL striatum and substantia nigra (SN)/midbrain, phosphorylated TrkB and secondary messengers were significantly increased following DHF compared to the MPTP only group. Expression of the sprouting biomarker, superior cervical ganglion 10 (SCG10), was increased ∼20% in the DL striatum and 66% in the SN/midbrain in mice treated with DHF compared to the MPTP only group. We report that after 4 weeks of progressive MPTP administration, DHF can restore motor deficits and TH within the DL striatum in a TrkB-dependent manner. Our data suggests that DHF may help alleviate motor symptoms of PD and restore the loss of DA terminals within the striatum.
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No medications are proven to slow the progression of Parkinson disease (PD). Of special concern with longer-standing PD is cognitive decline, as well as motor symptoms unresponsive to dopamine replacement therapy. Not fully recognized is the substantial accumulating evidence that long-term aerobic exercise may attenuate PD progression. Randomized controlled trial proof will not be forthcoming due to many complicating methodological factors. However, extensive and diverse avenues of scientific investigation converge to argue that aerobic exercise and cardiovascular fitness directly influence cerebral mechanisms mediating PD progression. To objectively assess the evidence for a PD exercise benefit, a comprehensive PubMed literature search was conducted, with an unbiased focus on exercise influences on parkinsonism, cognition, brain structure, and brain function. This aggregate literature provides a compelling argument for regular aerobic-type exercise and cardiovascular fitness attenuating PD progression.
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Behavioural neuroscienceEndurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of Parkinsonism with severe neurodegeneration

Abstract

Section snippets

Animals

Locomotor deficit and endurance exercise training

Discussion

Acknowledgments

Med Clin North Am

Arch Phys Med Rehabil

Biochem Biophys Res Commun

Neurosci Res

Gen Pharmacol

Brain Res

Arch Phys Med Rehabil

Neuroscience

Neuroscience

Exp Neurol

Am J Cardiol

Exp Gerontol

Neuroscience

Nonmotor complications in Parkinson’s disease

Mov Disord

Resting bradycardia of exercise training: A concept based on currently available data

Recent Adv Stud Cardiac Struct Metab

R wave amplitude during exerciseRelation to left ventricular function and coronary artery disease

Br Heart J

Aerobic exercise intervention improves aerobic capacity and movement initiation in Parkinson’s disease patients

NeuroRehabilitation

Behavioural neuroscience
Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of Parkinsonism with severe neurodegeneration