Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

Arnold, Jennifer C.; Salvatore, Michael F.

doi:10.1021/acschemneuro.5b00282

Cited by 18 publications

(27 citation statements)

References 73 publications

(260 reference statements)

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“…The treadmill exercise regimen followed a footshock-free exercise training regimen [ 28 , 33 ]. The exercise regimen consists of three separate phases: pre-exercise, treadmill acclimation, and treadmill exercise.…”

Section: Methodsmentioning

confidence: 99%

“…One possible mechanistic link between exercise impact on aging and locomotor function is glial cell-derived neurotrophic factor (GDNF) signaling. GDNF reduces motor impairment in aged rats and primates [ 24 , 25 ] Exercise can increase GDNF expression [ 26 , 27 ] or expression of its receptor, GFRα1 [ 28 ], and these increases are linked to increased dopamine (DA) content and tyrosine hydroxylase (TH) expression in substantia nigra (SN) [ 26 , 28 ]. However, aging may be a barrier for this exercise impact on GDNF signaling.…”

Section: Introductionmentioning

confidence: 99%

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Aging-related limit of exercise efficacy on motor decline

et al. 2017

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Identifying lifestyle strategies and allied neurobiological mechanisms that reduce aging-related motor impairment is imperative, given the accelerating number of retirees and increased life expectancy. A physically active lifestyle prior to old age can reduce risk of debilitating motor decline. However, if exercise is initiated after motor decline has begun in the lifespan, it is unknown if aging itself may impose a limit on exercise efficacy to decelerate further aging-related motor decline. In Brown-Norway/Fischer 344 F1 hybrid (BNF) rats, locomotor activity begins to decrease in middle age (12–18 months). One mechanism of aging-related motor decline may be decreased expression of GDNF family receptor, GFRα-1, which is decreased in substantia nigra (SN) between 12 and 30 months old. Moderate exercise, beginning at 18 months old, increases nigral GFRα-1 and tyrosine hydroxylase (TH) expression within 2 months. In aged rats, replenishing aging-related loss of GFRα-1 in SN increases TH in SN alone and locomotor activity. A moderate exercise regimen was initiated in sedentary male BNF rats in a longitudinal study to evaluate if exercise could attenuate aging-related motor decline when initiated at two different ages in the latter half of the lifespan (18 or 24 months old). Motor decline was reversed in the 18-, but not 24-month-old, cohort. However, exercise efficacy in the 18-month-old group was reduced as the rats reached 27 months old. GFRα-1 expression was not increased in either cohort. These studies suggest exercise can decelerate motor decline when begun in the latter half of the lifespan, but its efficacy may be limited by age of initiation. Decreased plasticity of GFRα-1 expression following exercise may limit its efficacy to reverse motor decline.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aging-related limit of exercise efficacy on motor decline

et al. 2017

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“…Studies have reported that exercise improved mitochondrial function, reduced α-synuclein expression and reduced the production of pro-inflammatory factors in MPTP PD model, leading to attenuated DA denervation and motor function loss (Sung et al, 2012 ; Subramaniam and Chesselet, 2013 ; Goes et al, 2014 ; Kelly et al, 2014 ; Spielman et al, 2016 ; Jang et al, 2017 ; Koo et al, 2017a , b ). Here, we focus on neurotrophic factors (NTFs) because exercise increases NTFs in normal animals and humans and NTFs are neuroprotective and neurorestorative (Cotman et al, 2007 ; Voss et al, 2013 ; Arnold and Salvatore, 2016 ).…”

Section: Molecular Mechanisms Underlying Exercise-induced Neuroprotecmentioning

confidence: 99%

“…Besides supplying exogenous NTFs via an invasive surgery-infusion means, other methods that stimulate the production of endogenous NTFs can also be neuroprotective while avoiding the risks associated with intracranial infusion surgery. Research since the 1990's has indicated that physical activity or exercise can increase NTF production in normal animals and also in humans, although human studies are few and only serum NTFs were tested due to the difficulties in obtaining human tissue samples (Neeper et al, 1995 , 1996 ; van Praag et al, 1999 , 2005 ; Cotman and Berchtold, 2002 ; Cotman et al, 2007 ; Pereira et al, 2007 ; Voss et al, 2013 ; Coelho et al, 2014 ; Arnold and Salvatore, 2016 ; Marston et al, 2017 ).…”

Section: Molecular Mechanisms Underlying Exercise-induced Neuroprotecmentioning

confidence: 99%

Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

Hou

Chen

Liu

et al. 2017

Front. Aging Neurosci.

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Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD), and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA) system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN) dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise-induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients.

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“…Thus, N-acetylcysteine shows benefit via evaluation of glutathione in treatment of PD. The locomotor impairment is a common symptom in PD progression; Arnold and Salvatore indicate that short-term exercise can attenuate the locomotor impairment in aging rats via increasing nigral glial cell line-derived neurotrophic factor (GDNF) receptor, GFR- α 1, and EAAC1 expression in conjunction with increased nigral tyrosine hydroxylase expression [ 86 ]. We previously found that ceftriaxone can improve the cell viability, glutamate uptake, and GLT-1 expression in the membrane in neurotoxin MPP + -treated astrocytes [ 70 ].…”

Section: Eaats Are Potential Therapeutic Targets In Pdmentioning

confidence: 99%

Recent Advance in the Relationship between Excitatory Amino Acid Transporters and Parkinson’s Disease

Zhang

Tan

et al. 2016

Neural Plasticity

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Parkinson's disease (PD) is the most common movement disorder disease in the elderly and is characterized by degeneration of dopamine neurons and formation of Lewy bodies. Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). If glutamate is not removed promptly in the synaptic cleft, it will excessively stimulate the glutamate receptors and induce excitotoxic effects on the CNS. With lack of extracellular enzyme to decompose glutamate, glutamate uptake in the synaptic cleft is mainly achieved by the excitatory amino acid transporters (EAATs, also known as high-affinity glutamate transporters). Current studies have confirmed that decreased expression and function of EAATs appear in PD animal models. Moreover, single unilateral administration of EAATs inhibitor in the substantia nigra mimics several PD features and this is a solid evidence supporting that decreased EAATs contribute to the process of PD. Drugs or treatments promoting the expression and function of EAATs are shown to attenuate dopamine neurons death in the substantia nigra and striatum, ameliorate the behavior disorder, and improve cognitive abilities in PD animal models. EAATs are potential effective drug targets in treatment of PD and thus study of relationship between EAATs and PD has predominant medical significance currently.

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Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

Cited by 18 publications

References 73 publications

Aging-related limit of exercise efficacy on motor decline

Aging-related limit of exercise efficacy on motor decline

Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

Recent Advance in the Relationship between Excitatory Amino Acid Transporters and Parkinson’s Disease

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