BDNF as a Promising Therapeutic Agent in Parkinson's Disease

Abstract

Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson's disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance. Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed. Since, in both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway, it has been hypothesized that BDNF may serve as a therapeutic agent. Direct delivery of exogenous BDNF into the patient's brain did not relieve the symptoms of disease, nor did attempts to enhance BDNF expression with gene therapy. Physical training was neuroprotective in animal models of PD. This effect is mediated, at least partly, by BDNF. Animal studies revealed that physical activity increases BDNF and tropomyosin receptor kinase B (TrkB) expression, leading to inhibition of neurodegeneration through induction of transcription factors and expression of genes related to neuronal proliferation, survival, and inflammatory response. This review focuses on the evidence that increasing BDNF level due to gene modulation or physical exercise has a neuroprotective effect and could be considered as adjunctive therapy in PD.

Keywords: PD therapy; Parkinson’s disease; brain-derived neurotrophic factor; neurodegeneration; neuroprotection; physical exercise.

Figure 1

Signaling cascades activated by interaction of BDNF isoforms with two types of cell surface receptors, the p75 neurotrophin receptor and TrkB receptor. proBDNF has a greater affinity for the p75 receptor. The pro-BDNF/p75/sortilin complex leads to activation of JNK, RhoA, and NF-ĸB signaling pathways which promote processes such as apoptosis, neuronal growth cone development, and neuronal survival. The mBDNF/TrkB receptor complex triggers activation of three signaling pathways—MAPK, PI3K/Akt, and PLC-γ—that, in turn, activate the transcription factor CREB and transcription of genes responsible for development and survival of neurons. proBDNF— precursor of brain-derived neurotrophic factor, mBDNF—mature brain-derived neurotrophic factor, TrkB—tropomyosin receptor kinase B, JNK—c-Jun N-terminal kinases, RhoA—Ras homolog gene family member, NF-ĸB—nuclear factor kappa B, MAPK—mitogen-activated protein kinase, PI3K—phosphatidyl inositol-3 kinase, PLC-γ—phospholipase C-γ, CREB—cAMP response element-binding protein.

Figure 2

Summary of the major effects of BDNF delivery through direct injection and gene therapy before and after the induction of Parkinson’s disease (PD) in animal models. (A) BDNF signaling upregulation before the induction of PD prevented dopaminergic cell loss in SN and the loss of dopaminergic projections to ST. BDNF stimulation elevated the DA level in SN and ST, and DA uptake in ST. To the best of our knowledge, studies concentrating directly on synaptic plasticity were not conducted. (B) BDNF delivery after induction of PD did not alter the number of dopaminergic neurons; however, it induced dopaminergic axon regrowth, increased synaptic plasticity, and elevated the DA level in ST, but not in SN. To our knowledge, DA uptake was not studied in this BDNF administration paradigm. Exceptions to the rules: ¹ Lack of neuronal cells preservation by BDNF treatment before PD induction [90,91]. ² Lack of effect on TH+ fibers in ST by BDNF treatment after PD induction [97,98]. BDNF—brain-derived neurotrophic factor, DA—dopamine, PD—Parkinson’s disease, SN—substantia nigra, ST—striatum.

Figure 3

The molecular and physiological changes caused by exercise in animal models of Parkison’s disease. Physical effort led to an increase in BDNF level, TH-ir cell number and TH protein content in SN, TH-ir fibers intensity in ST, and DA content in SN and/or ST. The results from DOPAC content analysis in the brain were contradictory. Training also increased the level of TrkB in SN and hippocampus, but not in ST. In addition, exercise increased the DAT level in ST, VMAT staining intensity in SN. Physical activity was able to maintain mitochondrial integrity and respiratory function in ST, elevate neurogenesis in subventrical zone and migration of neurons toward the place of lesion, and decrease oxidative stress. BDNF—brain-derived neurotrophic factor, TrkB—tropomyosin receptor kinase B, SN—substantia nigra, ST—striatum, DA—dopamine, TH—tyrosine hydroxylase, DOPAC—3,4-Dihydroxyphenylacetic acid, DAT—dopamine active transporter, VMAT—vesicular monoamine transporter.

Figure 4

Systemic (I) and central nervous system (II) responses to physical exercise. (I) Physical exercise promotes angiogenesis and neuroplasticity, and anti-oxidation counteracts oxidative stress. (II) Physical exercise increases BDNF affinity to the TrkB receptor (1) enhancing a cascade of intracellular signals, including MAPK/ERK1/2–IP3/Akt pathway (2) that inhibits apoptosis and free radical release—ROS (A) on the one hand, and phosphorylation of transcription factor CREB on the other (3); the latter, by attaching to the CRE elements in the cell nucleus, increases the transcription of the tyrosine hydroxylase gene (4) responsible for conversion of tyrosine to L-DOPA, from which DA is formed, and transcription of genes (5) that promote the survival processes, thereby blocking apoptosis and inhibiting the formation of ROS (B). Akt—Akt enzyme, also known as protein kinase B, BDNF—brain-derived neutrophic factor, CREB—cyclicAMP-response element-binding protein, DA—dopamine, ERK—extracellular signal-regulated kinases, IP3—inositol trisphosphate, L-DOPA—levodopa, MAPK—mitogen-activated protein kinase, ROS—reactive oxygen species, TrkB—tropomyosin receptor kinase B.