Neuroinflammation and cytokine-dependent neurotoxicity appear to be major contributors to the neuropathology in Parkinson’s disease (PD). While pharmacological advancements have been a mainstay in the treatment of PD for decades, it is becoming increasingly clear that nonpharmacological approaches including traditional and nontraditional forms of exercise and physical rehabilitation can be critical adjunctive or even primary treatment avenues. Here, we provide an overview of preclinical and clinical research detailing the biological role of proinflammatory molecules in PD and how motor rehabilitation can be used to therapeutically modulate neuroinflammation, restore neural plasticity, and improve motor function in PD.
PD is the second most common neurodegenerative disorder generally affecting the population over 65. In fact, only 4% of cases occur before the age of 50 [
However, recently, postmortem brain imaging and fluid biomarker investigations identified neuroinflammation as a crucial pathogenesis factor of PD [
To reach the aim of this study, publication search for literature review was conducted using the NCBI PubMed database based on the following groups of keywords: (1) Parkinson’s disease, pro-inflammatory cytokines; (2) Parkinson’s disease, IL-6, IL-1
Brain cytokine activity depends on several conditions such as the cellular sources and the pathophysiological context all contributing to the effects exerted on the brain. In fact, cytokines can promote apoptosis of neurons, oligodendrocytes, and astrocytes; cause damage to myelinated axons; but even initiate neuroprotective effects, independently of their immunoregulatory properties [
Among cytokines, interleukin-6 (IL-6), IL-1
IL-1
It has been demonstrated that IL-1
Nonetheless, Saura and colleagues have demonstrated that an acute infusion of a high dose (20 ng) of IL-1
IL-6 is a member of the neuropoietic cytokine family with a wide range of biological activities. It is involved in the development, differentiation, degeneration, and regeneration of neurons in the central and peripheral nervous systems and can also stimulate glial cells [
In regard to the expression of IL-6 in PD, there are some controversial results. Several studies observed an increase of IL-6 in the nigrostriatal region of the postmortem brain and in CSF of PD patients [
IL-8 is a chemoattractant cytokine secreted by a variety of cells (e.g., monocytes [
MCP-1 (CCL2), one of the most highly and transiently expressed chemokines during inflammation, is a member of the CC subtype chemokines. MCP-1 exerts its biological functions by binding to its high-affinity receptor, CCR2, which is mainly expressed by microglia, astrocytes, and brain microvascular endothelial cells (BMECs) in the brain [
Several studies have demonstrated that MCP-1 is constitutively present in the brain. The neuronal expression of MCP-1 is mainly found in the cerebral cortex, globus pallidus, hippocampus, lateral hypothalamus, Purkinje cells, cerebellum, astrocytes, perivascular microglia, infiltrating leukocytes, cholinergic neurons of magnocellular preoptic, and in dopaminergic neurons of the substantia nigra pars compacta [
Additionally, MCP-1 may modulate the function of the BBB components and thus affect the integrity of BBB. In accordance with this hypothesis, the MCP-1 level has been found to positively correlate with the permeability of the BBB and progression of diseases [
It has also been established that MCP-1 is an important mediator in several neuroinflammatory and neurodegenerative brain diseases characterized by neuronal degeneration such as PD.
MCP-1 levels in the blood are heightened in PD subjects compared to controls and correlate with PD progression [
Furthermore, it has been shown that MCP-1 could be implicated not only in disease progression but also in pathogenesis. The Ccl2-2518A allele is associated with lower MCP-1 production and reduced transcriptional activity following IL-1
TNF-
High levels of TNF-
Knock-out mice for the TNF-
However, TNF-
Several
In experiments where TNF-
Taken together, these results indicate that long-term expression of proinflammatory levels of TNF-
Specific rehabilitation programs, as a support to pharmacological therapies in the treatment of parkinsonian patients, were proposed in 1956 [
Studies on the neuroprotective effects of physical exercise introduced forced or voluntary exercise before, during, or immediately after administration of the toxins (6-OHDA or MPTP) and reported improved motor functions, along with the preservation of dopaminergic neurons and the restoration of dopaminergic terminals in the striatum. These improvements have been mainly attributed to either an increased level of neurotrophic factors such as BDNF or GDNF [
Neurorestoration is suggested as another exercise-induced process for recovery of behavioural functions, and it does not involve neuroprotection [
Physical exercise also modulates glutamatergic neurotransmission. Among the crucial aspects underlying motor impairment in individuals with PD, there is the hyperexcitability in the indirect pathway induced by dopamine depletion in the striatum in response to alterations in glutamate receptor expression and neurotransmitter release [
In summary, exercise is generally accepted as an intervention that could help both motor and nonmotor complications of PD, but it should be emphasized that not all types of rehabilitation approaches could facilitate neuroplasticity and behaviour in individuals with PD. Indeed, experience-dependent neuroplasticity is largely dependent on the intensity, repetition, specificity, difficulty, and complexity of the practice, and it is very likely that patients with PD need more time to achieve effective learning and automation. A precedent study by Frazzitta and colleagues [
The study of Tinazzi and colleagues (2019) based on a four-week trunk-specific exercise program in PD patients with pronounced forward trunk flexion has confirmed the importance of intensive and specific physiotherapy. Rehabilitative protocols lasted 4 weeks (60 min/day, 5 days/week) and have led to improved passive and active control of the trunk that was maintained at one month post treatment [
Similarly, Corcos and colleagues [
Here, we intend to focus on the effects of exercise on altered levels of proinflammatory cytokines and GDNF and BDNF.
Neurotrophins are a group of proteins having the ability to stimulate survival, cell growth, and maintenance of the functional capacities of specific neuronal populations [
The most studied neurotrophic factors in PD are GDNF and BDNF.
GDNF is a neurotrophic factor purified for the first time from a rat glioma cell line (B49) [
Furthermore, studies performed on rat and mouse models of PD showed the neurorestorative properties of GDNF [
Furthermore, the trophic effects of GDNF have been described as TGF-
Because of these promising effects on PD, researchers have investigated several means able to increase GDNF levels.
The direct delivery of GDNF to the brain region affected in PD seems to optimize the chances of obtaining therapeutic efficacy. Using different viral vectors and different animal models including adeno-associated viral vectors (AAV) in rat models of PD [
So far, the clinical evaluations of GDNF treatments in patients with PD have been inconsistent, potentially due to insufficient distribution of GDNF throughout the nigrostriatal system [
Thus, long-term targeted release of GDNF over the majority of the nigrostriatal system could represent an interesting and attractive option for treatment of PD.
Another valuable ally for increasing GDNF release is physical exercise [
The other most studied neurotrophic factor in PD is BDNF. BDNF supports the survival and the differentiation of dopaminergic neurons and protects them from neurotoxin-induced degeneration [
A research field in continuous development focuses on studying the effects of exercise on BDNF level changes in healthy adult populations [
Exercise-induced BDNF release seems to carry out a crucial role in neuroplastic effects of rehabilitation interventions in humans with neurodegenerative disease, particularly with PD [
In fact, it seems that BDNF plays a complicated role in both LTP and LTD and contributes in different ways to short-term and long-term plasticity: initially, the pro-BDNF binds to two postsynaptic receptors: the tyrosine kinase B (TrkB) receptor and the p75 receptor. TrkB activation facilitates the induction of LTP [
In order to explore if the neuroprotection offered by exercise is BDNF-dependent, Gerecke and colleagues (2010) studied the effectiveness of voluntary physical training with a running wheel in mice on a 90-day program. Mice were divided into two groups: mice with heterozygous deletion of the BDNF gene and wild-type mice. Only the second group showed neuroprotection against exposure to the toxin inducing dopamine cell loss [
A different research team has demonstrated that physical exercise reduces the 6-OHDA-induced damage acting on BDNF receptors. In fact, blocking of BDNF receptors causes enhanced postlesion nigrostriatal dopaminergic cell loss, quantified as a reduction in the expression of TH [
Finally, clinical data on the impact of physical exercise on reducing PD-related proinflammatory cytokine levels received increasing attention over recent years; in particular, investigations focus on the modulation of inflammatory markers as potential molecular mechanisms involved in the beneficial effects of exercise on PD patients.
Cadet and colleagues showed that cyclical exercise, performed for months, leads to a significant increase in the plasma level of anti-inflammatory signal molecules, such as interleukin-10 (IL-10) and adrenocorticotropin, while plasma levels of proinflammatory cytokines such as IL-1 and IL-6 were not affected. Additionally, this cyclic exercise protocol has also been shown to improve fine motor skills. These data suggest that cyclical exercise induces the formation of anti-inflammatory signalling molecules, which appear to be associated with relieving of some clinical impairments of PD [
Two more recent studies (years 2017 and 2018) also showed that alternative and not traditional physical exercises such as Qigong, an oriental mind-body exercise, or physical exercise in water can improve the inflammatory state of PD.
In this study by Moon and colleagues, ten subjects with PD were recruited and then randomly assigned to one of the two groups who received six weeks of Qigong intervention (experimental group) or sham Qigong (control group). After the intervention, the serum level of TNF-
Pochmann and colleagues instead focused on exploring the molecular mechanisms underlying the improvement of motor symptoms and functional mobility in water-based exercise interventions in patients with PD. The authors reported higher levels of the proinflammatory cytokines IL-1
In conclusion, both traditional and not traditional forms of exercise have been shown to be important for improving motor function, facilitating neuroplasticity, and reducing neuroinflammation in PD. Further investigations are needed to broaden our knowledge on the mechanisms through which specific physical training induces neuroplasticity, eventually leading to a deeper knowledge of its role in interfering with the disease progression and to identify novel therapeutic targets to finally improve the effects of pharmacological approaches of PD.
Alzheimer’s disease
Amyotrophic lateral sclerosis
Artemin
Adeno-associated viral vectors
Blood-brain barrier
Brain-derived neurotrophic factor
Brain microvascular endothelial cells
Cornu Ammonis area 1
Central nervous system
cAMP response element-binding protein
Cerebrospinal fluid
Dopaminergic neurons
Dopamine transporter
Extracellular signal-regulated kinase
Focal adhesion kinase
Nonreceptor tyrosine kinase Fyn
Glial cell line-derived neurotrophic factor
GDNF family receptor-
GDNF family receptor
GDNF family
Janus kinase- (JAK-) signal transducer and activator of transcription (STAT)
Interferon-
Interleukin-1
Interleukin-2
Interleukin-6
Interleukin-8
Interleukin-10
L-DOPA-induced dyskinesia
Lipopolysaccharide
Long-term depression
Long-term potentiation
Mitogen-activated protein kinase
Monocyte chemotactic protein-1
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Multiple sclerosis
Neural cell adhesion molecule receptors
N-Methyl-D-aspartate receptor
Neurturin
6-Hydroxy dopamine
Phosphoinositide 3-kinase
Reactive nitrogen species
Reactive oxygen species
Substantia nigra
Parkinson’s disease
Positron emission tomography
Protein kinase B
Persephin
Rat sarcoma virus GTP-binding protein
REarranged during Transfection
Transforming growth factor
Tyrosine hydroxylase
Tumor necrosis factor-
Tyrosine kinase B
Unified Parkinson’s Disease Rating Scale score.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The study was supported by the University of Verona Basic Research Grant, awarded to Giovanna Paolone Grant ID: RIBA 2019.