Brain-derived neurotrophic factor (BDNF) is a specific neurotrophic factor that provides developmental aid to neurons in the nervous system [
51]. It stimulates the growth of new neurons and aids in the maturation and survival of existing neurons [
51]. BDNF has been shown to protect neurons from various conditions, including cerebral ischemia and hypoglycemia [
51]. PD is characterized by the loss of dopaminergic neurons, and studies have demonstrated that BDNF levels are lower in patients with PD [
52]. Mogi and colleagues (1999) [
52] found that in patients with PD, there was a significant decrease in BDNF levels in the nigrostriatal dopamine regions compared to healthy controls. Since BDNF confers neuroprotective properties, increasing and maintaining high levels of BDNF in patients with PD may be a potential therapeutic strategy. As per mouse models, activation of the BDNF signalling pathway could protect against loss of dopaminergic neurons in the substantia nigra [
53]. This is also supported by a rat study which included a group with BDNF receptor blockade, causing the exhibition of the neuroprotective effects of BDNF to be lower compared to the control group with respect to the damage done to the dopaminergic system [
54].
Exercise and Brain-derived neurotrophic factor (BDNF)
A potential explanation underlying the improvement in sleep parameters due to exercise is the positive correlation between physical activity and BDNF levels in the brain. Sleiman et al. (2016) showed how exercising mice increased the production of β-hydroxybutyrate in the liver, which then travelled to the brain and inhibited histone deacetylase [
55]. Histone deacetylases are a group of enzymes that remove acetyl groups from the amino acid lysine [
56], and research demonstrates that histone deacetylase inhibitors, not only provide their own neuroprotective effects [
56], but also help increase BDNF levels in the brain [
55,
56]. These changes may help to better understand the neurological benefits associated with exercise, such as improving neurogenesis and neuroplasticity, and decreasing neuroinflammation and sleep impairments associated with PD.
Research has shown how BDNF may be a mediating molecule for the potential relationship between exercise and neurogenesis [
57], a process that helps form new neurons in the brain [
58]. Exercise and BDNF have been shown to promote growth and survival of neurons, thereby helping to recover various motor behaviours and decrease motor symptoms [
59]. Hirsch et al. (2018) provides evidence for exercise increasing BDNF levels in the blood [
59]; however, the underlying cause of exercise-induced BDNF remains elusive [
60]. It is important to note that more research is still required to understand neurogenesis in patients with PD [
58], as well as the potential impact of exercise-induce BDNF on neurogenesis.
Exercise also improves neuroplasticity [
61], which is the brain’s ability to promote the formation and development of neural pathways. Neuroplasticity can be due to psychophysiological or environmental stimulation and results in functional or structural changes [
61]. Kempermann et al. (2018) demonstrated that an increase in neurotrophins, such as BDNF, results in an increase in neuroplasticity [
62]. Because of this finding, with the increases in BDNF following either acute or regular exercise [
63], studies have found a potential correlation between exercise-induced BDNF and increases in neuroplasticity [
59,
61,
62,
64]. For example, three cognitive rehabilitation sessions per week for one month in patients with PD involving paper and pencil exercises have shown improvements in serum BDNF levels and cognition [
65]. The underlying mechanism explaining this correlation involves BDNF binding to its receptors, which results in the release of intracellular signals and subsequent phosphorylation of cAMP-response element-binding protein [
60], a protein that regulates the expression of genes in dopaminergic neurons [
66]. This phosphorylation increases the expression of tyrosine hydroxylase, an enzyme that helps convert the amino acid tyrosine into dopamine, resulting in exercise-dependent neuroplasticity [
60].
Exercise has also been shown to aid in mitochondrial function and reduce neuroinflammation, which has been associated with PD [
67]. Mitochondrial dysfunction in patients with PD can lead to apoptosis and oxidative stress due to the inhibition of complex I, causing an increase in reactive oxygen species and the destruction of dopaminergic neurons [
68]. A mouse model showed that exercise can reduce the build-up of α-synuclein, along with increasing BDNF and heat shock protein (Hsp70) [
69]. This is an important finding as it shows the therapeutic potential of exercise in patients with PD who have been shown to express low serum BDNF levels and increased α-synuclein levels, which has contributed to cognitive deficits [
70,
71].
Treadmill exercise has also been shown to reduce impairments in striatal dopaminergic neurons and reduce oxidative damage in a rodent model of PD [
72]. A mouse model of PD with moderate neurodegeneration showed that treadmill exercise reduced the loss of neuronal dopamine-producing cells and increased mitochondrial function and region-specific BDNF levels [
73]. High-intensity exercises, which combine resistance training, aerobic training, and balance training, have been shown to increase mitochondrial complex activity [
74], and lower-intensity exercises, such as walking, have been shown to increase maximum oxygen consumption [
75]. Other chemical enhancements suggest increases in neural health due to aerobic treadmill exercises increasing levels of BDNF, neurogenesis, and the clearance of α-Synuclein [
76]. Furthermore, moderate-intensity balance training has been shown to affect immune function in patients with PD, specifically by decreasing tumor necrosis factor-alpha [
77].
Exercise modalities can be very important to assess since results show that high-intensity exercise combining both aerobic and resistance training increased BDNF levels more compared to moderate-intensity [
78]. It has been suggested that increasing heart rate and oxygen demand can be beneficial when carefully monitored by a medical professional [
79]. Both continuous and high-intensity cycle exercises have also been shown to increase serum BDNF in healthy humans; however, high-intensity exercises have been shown to result in greater BDNF concentrations [
80].
Sleep and BDNF
Sleep is associated with various neurochemical substances, including BDNF [
81]. Although the mechanism remains unclear, altered BDNF levels have been shown to significantly influence sleep parameters [
81]. A rat model found a strong positive correlation between BDNF in the pedunculopontine tegmentum and homeostatic drive towards REM sleep [
82], suggesting that BDNF has a strong physiological mechanism to help increase REM sleep.
BDNF appears to be associated with sleep, as rat models have shown that microinjections of BDNF can result in increased slow-wave activity, and microinjections of the inhibitor of BDNF TrkB receptors resulted in decreased slow-wave activity [
83]. Low BDNF levels were shown to be associated with low SWS and REM sleep in sleep-disordered patients [
84].
Moreover, a study which induced microinjections of BDNF in awake rats at the prefrontal cortex showed significant increases in slow-wave activity during sleep, whereas the introduction of BDNF blockers resulted in decreased slow-wave activity [
83]. This effect did not impact the duration of sleep and was reversible post-NREM [
83]. Similarly, other research has found that BDNF levels during waking hours are directly correlated with SWS [
85]. Therefore, it follows that if exercise can increase BDNF levels, it can increase slow-wave activity in patients with PD, resulting in better sleep. Nevertheless, the underlying mechanism(s) explaining the correlation between BDNF and SWS remains ambiguous and requires more research [
85].