Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

Abstract

Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/−) with strain-matched wild-type (WT) mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/− mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/− mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

Intermittent metabolic switching, neuroplasticity and brain health

“…Autonomic dysfunction in these mice is ameliorated by ADF and exacerbated by excessive caloric intake 150 . Enhancing neurotrophic support (BDNF and glial-cell-line-derived neurotrophic factor), induction of protein chaperones, ketogenesis and ghrelin signalling are among the neuroprotective mechanisms of action of IMS suggested from the experiments with PD animal models 151–153 .…”

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment

“…The mechanisms by which exercise induces upregulation of D2/ D3 receptors have been investigated in animal models of striatal dopaminergic injury, modeling Parkinson's disease physiology. In rodents, wheel running after stimulant exposure produces significant changes in gene transcription factors capable of modulating dopaminergic neurotransmission in the mesolimbic pathways (Greenwood et al, 2011;Zlebnik et al, 2014), and wheel running attenuates MPTPinduced damage to dopaminergic cells in wild-type mice, but not in BDNF (+/ − ) knockdown mice (Gerecke et al, 2012). Similarly, BDNF receptor antagonists blocked the effects of treadmill running against damage to dopaminergic neurons, as indicated by preserved levels of tyrosine hydroxlase activity, in a rat model of Parkinson's disease using striatal injection of 6-hydroxydopamine (Real et al, 2013).…”

Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease

“…These studies have reported improvement in motor function, along with the preservation of DA neurons and the restoration of dopaminergic terminals, using tyrosine hydroxylase (TH) immunostaining, within the striatum. In these toxin models, neuroprotection has been principally attributed to an exercise-induced increase of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) 78–81 . An alternative mechanism for neuroprotection of these models may be though the exercise induced down regulation of DAT, the primary uptake system for 6-OHDA and MPTP 73, 75 .…”