Exercise protects against MPTP-induced neurotoxicity in mice

Gerecke, Kimberly M.; Jiao, Yun; Pani, Amar K.; Pagala, Vishwajeeth; Smeyne, Richard J.

doi:10.1016/j.brainres.2010.01.053

Cited by 99 publications

(109 citation statements)

References 107 publications

(121 reference statements)

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“…56,57 4. Midbrain dopaminergic neuronal counts corroborated a neuroprotective effect from exercise in some, 53,58 but not in all studies. 52,56 5.…”

Section: Animal Modelsmentioning

confidence: 80%

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Does vigorous exercise have a neuroprotective effect in Parkinson disease?

2011

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Parkinson disease (PD) is progressive, with dementia and medication-refractory motor problems common reasons for late-stage nursing-home placement. Increasing evidence suggests that ongoing vigorous exercise/physical fitness may favorably influence this progression. Parkinsonian animal models reveal exercise-related protection from dopaminergic neurotoxins, apparently mediated by brain neurotrophic factors and neuroplasticity (predicted from in vitro studies). Similarly, exercise consistently improves cognition in animals, also linked to enhanced neuroplasticity and increased neurotrophic factor expression. In these animal models, immobilization has the opposite effect. Brain-derived neurotrophic factor (BDNF) may mediate at least some of this exercise benefit. In humans, exercise increases serum BDNF, and this is known to cross the blood-brain barrier. PD risk in humans is significantly reduced by midlife exercise, documented in large prospective studies. No studies have addressed whether exercise influences dementia risk in PD, but exercised patients with PD improve cognitive scores. Among seniors in general, exercise or physical fitness has not only been associated with better cognitive scores, but midlife exercise significantly reduces the later risk of both dementia and mild cognitive impairment. Finally, numerous studies in seniors with and without dementia have reported increased cerebral gray matter volumes associated with physical fitness or exercise. These findings have several implications for PD clinicians. 1) Ongoing vigorous exercise and physical fitness should be highly encouraged. 2) PD physical therapy programs should include structured, graduated fitness instruction and guidance for deconditioned patients with PD. 3) Levodopa and other forms of dopamine replenishment therapy should be utilized to achieve the maximum capability and motivation for patients to maintain fitness. Neurology Parkinson disease (PD) is progressive. Although the dopaminergic nigrostriatal system receives much attention, progression in nondopaminergic circuits eventually becomes the primary substrate for major PD disability. Nursing home placement is typically the consequence of cognitive impairment/dementia or nondopaminergic motor deficits, especially levodopa-refractory balance and gait problems. 1A major focus of PD research has been on "disease-modifying" or "neuroprotective" agents to slow PD progression. No drugs have surfaced, to date, that unequivocally have that property. However, often overlooked in this discussion is the potential benefit of sustained vigorous exercise on PD progression. Exercise is well-known to have general health benefits, including improvement of cardiovascular and cerebrovascular health, reduction of osteoporosis/fracture risk and age-related sarcopenia, improvement of psychological affect, and perhaps even a general anti-inflammatory effect.2 However, accumulating evidence, albeit indirect, suggests that ongoing vigorous exercise may have a neuroprotective effect in PD, beyond th...

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“…56,57 4. Midbrain dopaminergic neuronal counts corroborated a neuroprotective effect from exercise in some, 53,58 but not in all studies. 52,56 5.…”

Section: Animal Modelsmentioning

confidence: 80%

“…There is a dose effect, with exercise duration and intensity each influencing the neurochemical and neuronal count results, as well as the motorparkinsonism. 53,58 6. Exercise attenuates the hyperexcitability of striatal (medium spiny) neurons after dopamine depletion, with modulation of glutamatergic receptor subunit expression.…”

Section: Animal Modelsmentioning

confidence: 99%

Does vigorous exercise have a neuroprotective effect in Parkinson disease?

2011

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“…Many studies have supported the long-term benefits of exercise in humans, even in Alzheimer's and Parkinson's patients Xu et al 2010;Erickson et al 2012;Mayeux and Stern 2012;Fisher et al 2013;Intlekofer and Cotman 2013;Winchester et al 2013). Animal studies have also shown convincingly that exercise is protective in experimental models of neurodegeneration (for some examples, see Adlard et al 2005;Nichol et al 2009;Pothakos et al 2009;Zigmond et al 2009;Gerecke et al 2010;Vuckovic et al 2010;Intlekofer and Cotman 2013;Souza et al 2013). The studies on the benefits of long term exercise, dietary phytochemicals such as nicotine and caffeine, and moderate alcohol consumption all suggest that chronic adaptation to stress may be achievable in humans.…”

Section: Adaptation and Sensitization To Proteotoxic Stressmentioning

confidence: 99%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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ᮀ Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.

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“…However, despite the findings supporting the view that exercise protects against the behavioral effects of 6-OHDA and MPTP, data on the protection of dopaminergic neurons from 6-OHDA-or MPTP-induced toxicity are mixed (Zigmond et al, 2009). It has been reported that running for 3 months prior to acute MPTP administration completly protects from TH cell loss www.intechopen.com (Gerecke et al, 2010). On the other hand, exercise for 2 weeks after intrastriatal injection of 6-OHDA results in partial recovery of TH labeling and axonal fiber projection to the striatum (Yoon et al, 2007).…”

Section: Exercising For Gdnf Expression?mentioning

confidence: 99%