Brain-derived neurotrophic factor (BDNF) plays an essential role in neuroregeneration and neuroprotection

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Brain Derived Neurotrophic Factor (BDNF) is a key molecule involved in plastic changes related to learning and memory. The expression of BDNF is highly regulated, and can lead to great variability in BDNF levels in healthy subjects.

Changes in BDNF expression are associated with both normal and pathological aging and also psychiatric disease, in particular in structures important for memory processes such as the hippocampus and parahippocampal areas. Some interventions like exercise or antidepressant administration enhance the expression of BDNF in normal and pathological conditions.

The main finding of our study is that physical exercise significantly increases baseline serum levels of BDNF in PwMS. Subgroup analysis did not reveal any significant difference due to the type of exercise and the duration of the exercise training program.

Our meta-regression suggested that the existing heterogeneity in the meta-analysis results was not significantly related to sex or chronological age. It is plausible that variations in the quality of included studies could partially explain the existed heterogeneity in the meta-analysis results.

Variations in the BDNF measurement procedures and techniques (as pointed out in the study by Hirsch et al. [49]), protocol and settings of physical activity programs, and the ratio of included participants with RRMS or progressive MS in the included investigations might be other contributors to the heterogeneity in the meta-analysis results.

We were not able to evaluate the association between exercise program intensity and session time and changes in baseline peripheral BDNF concentrations. As all studies reported serum concentrations of BDNF, it is plausible that resting peripheral BDNF concentration is not a source of heterogeneity in this analysis.

Several pieces of evidence suggest that physical activity contributes to CNS functioning through multiple mechanisms [50–52], including (1) increasing cerebral blood flow, (2) endocannabinoid and neurotransmitter modulation, (3) alterations in neuroendocrine responses, and (4) structural changes in the CNS [50–52].

Given that exercise increases BDNF levels, this has been regarded as one of the potential mechanisms by which exercise affects brain health and functioning. BDNF improves synaptic potentiation, synaptic plasticity, and neuronal activity, also modifying axodendritic morphology [7,53,54]. In addition, BDNF enhances quantal neurotransmitter release by influencing presynaptic terminals, which potentiates synaptic transmission [55].

Exercise-induced increase of BDNF levels can contribute to plastic changes following physical activity [7,56]. Although no previous study has simultaneously investigated BDNF and neuroimaging changes after exercise in PwMS, several studies have demonstrated the effect of exercise in brain structure.

Prakash et al. [57] used a cross-sectional design to demonstrate that aerobic exercise affects both grey matter volume and white matter integrity in PwMS. Klaren et al. [58] reported that the volume of several areas of the brain, including the hippocampus, thalamus, caudate, putamen, and pallidum, relates to the level of moderate/vigorous physical activity. Kjølhede et al. [59] showed that the trend of reduced brain atrophy is nonsignificant in PwMS who attended a six months (2 days/week) resistance training program.

Multiple central and peripheral factors, influence the levels of BDNF [10]. In MS, treatment [60,61], sex [62], age [63], body mass index (BMI) [64], and disease status, as assessed by EDSS [65,66], have been associated with the peripheral levels of BDNF. Our results confirm that physical activity can also influence BDNF levels in PwMS. As the increase in serum levels of BDNF may reflect both peripheral and CNS changes [2], it remains to be determined the main source and/or target of these enhanced BDNF levels.

A previous meta-analysis of studies measuring BDNF after exercise in healthy adults revealed that aerobic training can increase BDNF concentrations more than resistance training [12]. Moreover, the duration of exercise was highly associated with BDNF increase [10]. In contrast, our subgroup meta-analysis considering the type of intervention (aerobic vs. resistance training) and duration of exercise (less than 12 weeks vs. 12 weeks or more) showed no significant difference in test for between-groups differences (random-effects model).

Frequency, intensity, duration, and mode of exercise are essential variables in the context of achieving positive rehabilitation outcomes for adults with MS [67,68]. Our subgroup meta-analysis considering the type of intervention (aerobic vs. resistance training) and duration of exercise (less than 12 weeks vs. 12 weeks or more) showed no significant difference in test for between-groups differences (random-effects model).

Recent interest in High Intensity Interval Training suggests that alternative exercise modalities may also offer promise in inducing BDNF related neuroplasticity in PwMS [69,70].

Collectively, reported data on the benefits of physical therapy and exercise on cognitive functions, including memory, learning, information processing, attention, and concentration, is noteworthy [71–75]. Numerous research have been conducted to date on the function of BDNF in the acute exercise—cognition connection [76–82].

Although all these studies corroborate the positive effects of acute exercise on cognitive performance, discrepancies exist in the proof that BDNF is responsible for these cognitive advantages [83]. Considering the previously-mentioned studies, exercise-induced alterations in BDNF and its correlation with cognitive performance were specifically tested by Ferris et al. [76], Lee et al. [79], Skriver et al. [80], Tsai et al. [82], and Winter et al. [78].

Additionally, substantial correlations between acute exercise-induced modifications in BDNF concentration and cognitive function have been reported in research measuring memory, but not in studies investigating non-memory aspects of cognition [83]. Regarding the beneficial effects of aerobic exercise, a case study by Leavitt et al. [84] reported a 16.5% increase in hippocampal volume following a 53% improvement in their memory after a 12-week aerobic exercise (30 min, 3 days/week).

A systematic review addressing studies on MS and cognition exhibited that out of eight included studies, five studies showed that exercise positively impacts patients’ cognitive status [8]. Additionally, BDNF Val66Met polymorphism has shown protective roles against cognitive impairment in PwMS [85]. Moreover, evidence indicates the neurotrophic role of BDNF on motor-related neurons, which may relieve motor symptoms via modulating neuronal morphology and motility [86].

There is some evidence suggesting that exercise may reduce MS progression. Regarding this association, intense exercise has shown reductions in MS development, excluding known factors and determinants of MS progression [87]. Still, long-term follow-up studies are needed to confirm these findings. In addition, based on pieces of evidence given in a systematic review, physical exercise training may reduce the risk of relapse in PwMS by 27% in the training group versus the control group [9]. However, a lack of papers with standard methodologies assessing the association of exercise training and MS progression exists in the current literature.

Notably, for other neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), exercise-induced BDNF has been proposed as a protective factor. For example, a meta-analysis of two randomized controlled trials and four pre-experimental studies with a total of 100 patients with PD undergoing physical exercise showed a significant increase in BDNF blood levels in parallel with improvement of motor symptoms (e.g., improvement in Unified Parkinson’s disease rating scale-Part III (MDS-UPDRS-III)) [49].

Another meta-analysis reporting the effects of exercise on neurotrophic factors in cognitively impaired individuals diagnosed with dementia or mild cognitive impairment (MCI) demonstrated positive and significant effects of exercise resulting in higher inflammatory and neurotrophic biomarkers in MCI patients [88].

Future studies should study the association between exercise, neuroplasticity markers and functional outcomes to determine whether the observed neurotrophic effects translate to clinical benefits. Ultimately, based on research findings, exercise may be an invaluable adjunct component to the existing medical treatments. Of note, more human studies are needed to underpin this relationship, as we cannot only rely on animal studies because of humans and animals’ structural and functional brain differences.

The main limitation of this current meta-analysis is that the extant studies on exercise in PwMS involved relatively small number of subjects. Other limitations include short-term interventions (<26 weeks), low levels of disability of most participants (EDSS scores <4), and the inclusion of mainly relapsing-remitting MS or mixed-group patient populations and exclusion of patients with comorbidities that could their relief assessed due to exercise training.

Moreover, we only included the intervention group of the included studies and analyzed the pre- and post-intervention levels of BDNF in PwMS who underwent exercise, as another meta-analysis conducted by Ruiz-González et al. [89] compared post-intervention levels of BDNF in both PwMS and controls.

It is worth emphasizing that Mackay et al. [90] intended to assess the impact of aerobic exercise on BDNF levels in persons with neurological disorders without segregating neurologic conditions (e.g., MS). Although they performed the meta-analysis considering all of the neurologic disorders, their results align with the current study and indicate that exercise might contribute to increased BDNF concentrations.


BDNF and its receptors

BDNF, which exists as a dimer, was first thought to only be present in the central nervous system (CNS) and synthesized by astrocytes; however, it has now also been detected in peripheral blood. BDNF dimers non-covalently bind to the membrane receptors to exert their biological effects. In general, both pre- and mature BDNF are able to bind and signal, albeit using two different families of receptors, namely the low-affinity p75 NT receptor (p75NTR) ‘panneurotrophic factor’ receptors (15-17) and the high-affinity tropomyosin associated kinase (TRK) receptors.

BDNF binds to the high-affinity TrkB (tyrosine kinase B) receptor of the TRK family (18), while p75NTR belongs to the tumor necrosis factor (TNF) receptor superfamily (17). p75NTR is thought to be a co-receptor for TrkB (19); however, its function has remained to be fully elucidated (20).

Studies suggest that p75NTR participates in pro-apoptotic processes during cell development (21), mediates the migration of Schwann cells (22) and determines the fate of certain non-neural cells (23). p75NTR, which was previously known for its weak binding, binds with high affinity to BDNF precursor (pro-BDNF), and subsequently, the resulting heterodimer binds to Sortilin, causing neuronal apoptosis and inhibition of axonal growth (24).

The other receptor, TrkB, is a transmembrane receptor with a tyrosine kinase domain encoded by the Trk proto-oncogene, which exists as either the full-length gp145TrkB or the truncated gp95TrkB (18). TrkB activation by BDNF stimulates neuronal activity, which is necessary for memory development and maintenance. The full-length gp145TrkB has a complex structure, including an extracellular binding domain for BDNF, a transmembrane region and a cytosolic tyrosine-kinase domain essential for BDNF signaling (Fig. 1).

The full-length gp145TrkB, upon autophosphorylation, exposes substrate binding sites for SHC, growth factor receptor-bound protein 2, ATP and phospholipase C (PLC)γ. In general, gp145TrkB activation triggers three downstream tyrosine kinase-mediated pathways, PLCγ1/PKC, MAPK-ERK and PI3/Akt, which regulate cell survival and differentiation (25). On the contrary, the truncated gp95TrkB, devoid of the tyrosine kinase domain, has a negative effect, which binds and internalizes BDNF without autophosphorylation (26). Of note, truncated gp95trkB may still mediate BDNF-induced cell proliferation but the mechanism has remained elusive. In this manner, TrkB affects both cell survival and BDNF production.

Figure 1 – BDNF signaling pathway. BDNF signaling via TrkB and p75NTR is complex. Activation of TrkB-FL by mature BDNF classically leads to activation of PLCγ and both the ERK pathway and the PI3K/Akt pathway promote cell proliferation and survival. In addition, TrkB may act through the NFκB pathway. In contrast to TrkB-FL, the truncated TrkB-T1 may be both inhibitory and activating via RhoA and PKC, resulting in cytoskeletal remodeling, gene modulation and other effects. The low-affinity p75NTR, when activated by mature BDNF, typically activates the pathway including TrkB-FL, but importantly, it may be inhibited via either the JNK or Akt pathways. This is particularly the case when p75NTR is activated by pro-BDNF and forms a ternary complex with the adaptor protein sortilin. BDNF, brain-derived neurotrophic factor; TrkB-FL, tyrosine kinase B full-length; PLC, phospholipase C; PKC, protein kinase C; NTR, neurotrophin receptor; CREB, C-response binding element; RhoA, ras homolog gene family, member A.

BDNF in autoimmune inflammatory diseases

Emerging evidence suggests that BDNF, as an immune function regulator, is linked to numerous autoimmune and inflammatory diseases, which is discussed in the following subsections (Table I).

Table I

BDNF and autoimmune inflammatory diseases.

Autoimmune diseaseSerum or tissueBDNF level in disease(Refs.)
Experimental autoimmune encephalomyelitis; multiple sclerosisT cells in the CNSStrong expression of BDNF in T cells near demyelinating lesions, suggesting that BDNF inhibited further parenchymal injury and participated in neuroinflammatory responses during repair. However, BDNF partially resists activation of T lymphocyte apoptosis, which may be the nature of chronic inflammatory processes.(11,39,40)
CDLocal intestinal lesionsLocal intestinal lesions in patients with CD with strong expression of BDNF and TrkB, and BDNF attenuated the apoptosis of glial cells to a small extent, protecting the integrity of the bowel.(41-43)
Ulcerative colitisLocal intestinal lesionsMassive inflammation was correlated with decreased neurotrophin immunoreaction in nerve structures and there was a tendency toward increased neurotrophin production in lamina propria cells.(44)
Pulmonary sarcoidosisT cells in bronchoalveolar lavatory fluidNGF and BDNF in CD4+ and CD8+ T lymphocytes in the lung were increased in pulmonary sarcoidosis. Expression of TrkB receptors was increased. There was a significant correlation between lymphocytosis, radiological stage and CD4 or CD8 NT expression.(45,46)
SScSerumLow serum BDNF level, particularly in diffuse SSc and in patients with pulmonary arterial hypertension or anti-Scl-70 antibodies.(47)
pSSSerumDecreased BDNF level in pSS with ILD. BDNF was correlated with the activation of B and T cells.(49,50)
RAPlasma and synovial tissue/SFHigher plasma BDNF level in RA, BDNF level in synovial tissue/SF was not correlated with the number of inflammatory cells or TNF-α or ESR, but plasma BDNF level was decreased 14 weeks after the initiation of anti-TNF therapy.(51)
SpAPlasma and synovial tissue/SFmRNA transcripts of all NTs and receptors were highly expressed in the inflamed synovium, correlating with vascularity and lymphoid aggregates. BDNF level was higher in the SF of patients with SpA than in OA.(52,53)
     SLESerum and plasmaSerum/plasma BDNF levels in SLE are correlated with SLEDAI scores and clinical parameters: C3, C4 and T-cell subsets. Serum BDNF levels may be decreased in active SLE.(9,55,59,60)

[i] BDNF, brain-derived neurotrophic factor; CNS, central nervous system; TrkB, tyrosine kinase B; NGF, nerve growth factor; NTs, neurotrophins; TNF, tumor necrosis factor; ILD, interstitial lung disease; ESR, erythroid sedimentation rate; OA, osteoarthritis; SLE, systemic lupus erythematosus; SF, synovial fluid; SLEDAI, SLE disease activity index; SpA, spondyloarthritis; RA, rheumatoid arthritis; pSS, primary Sjogren’s syndrome; SSc, systemic sclerosis; CD, Crohn’s disease; C3, complement component 3.

Table I – BDNF and autoimmune inflammatory diseases.

BDNF in EAE and MS

EAE is histologically and clinically similar to MS, which was established in an animal model to study autoimmune demyelination (11,39). Myelin-reactive T cells of the CNS produce and release BDNF to promote post-traumatic tissue repair (39). In both EAE and MS, T cells near demyelinating lesions significantly increase the expression of BDNF to inhibit the progression of neuron injury (39). By contrast, BDNF binding to TrkB-expressing T cells leads to evasion of T-lymphocyte apoptosis, which is a key event of the chronic inflammatory process in which T cells are involved (39).

Therefore, it is worthwhile determining whether T cell-derived BDNF promotes neuronal recovery or promotes the persistence of inflammation. A study reported that mice deficient in immune cells producing BDNF displayed attenuated immune response in the acute phase of EAE, which reduced further brain parenchymal injury but enhanced axonal loss in the chronic phase progressing into disability. Of note, transfection of T cells expressing BDNF strongly reduced brain damage in EAE and protected axons (40). Elevated serum BDNF levels have also been associated with nerve repair in patients with MS (11).

BDNF in inflammatory bowel diseases and pulmonary sarcoidosis

Steinkamp et al (41) reported increased expression of BDNF and TrkB in local intestinal lesions of Crohn’s disease (CD). In CD, enteric glial cells (EGCs) maintain the integrity of the bowel, while a loss of EGCs causes severe inflammation of the intestine. BDNF attenuates apoptosis of glial cells, while BDNF-neutralizing antibodies markedly increase apoptosis. Therefore, it is speculated that BDNF protects from CD by decreasing the apoptosis of EGCs.

Glial-derived neurotrophic factor promoting an anti-apoptotic loop in EGCs has a similar role to that in CD (42,43). Johansson et al (44) reported that NTs may also be involved in ulcerative colitis, in which massive inflammation exhibited a strong correlation with decreased NT immunoreaction. In addition, the production of NT increased in lamina propria cells. In pulmonary sarcoidosis, nerve growth factor (NGF) expression in alveolar macrophages increased with the increase in expression of NGF and BDNF in CD4+ and CD8+ T cells. An increased expression of TrkA, TrkB and TrkC receptors was also noticed. Furthermore, there was a significant correlation between the expression of NTs in CD4 or CD8 cell populations and the CD4:CD8 ratio, lymphocyte number, and radiological staging (45,46). Overall, these results suggested that increased levels of NTs in bronchoalveolar lavage fluid modulate the functions of immune cells in pulmonary sarcoidosis.

BDNF in connective tissue diseases

The role of BDNF in autoimmune diseases has been studied extensively. In systemic sclerosis (SSc), which is a microvascular disease, serum BDNF levels are decreased (47), particularly in diffuse SSc and in SSc with pulmonary arterial hypertension or anti-Scl-70 antibodies. Of note, BDNF and TrkB are also synthesized by capillary and arterial endothelial cells (48). Therefore, decreased BDNF levels in SSc may also be linked to microvascular disease and oxidative stress. Fauchais et al (49) and Li et al (50) studied serum BDNF levels in patients with primary Sjogren’s syndrome (pSS).

They detected high serum BDNF levels in pSS, which were correlated with the extent of systemic involvement. NGF and BDNF levels also correlated with the activation of B and T cells; specifically, the BDNF concentration was correlated with CD4+ T-cell activation assessed as human leukocyte antigen DR expression. Li et al (50) reported that, compared with patients with simple pSS or healthy controls, patients with pSS with interstitial lung disease (ILD) had lower serum BDNF levels, which may be used as a potential biomarker of ILD secondary to pSS. In rheumatoid arthritis (RA), plasma BDNF levels were increased; however, the concentration did not correlate with the number of inflammatory cells, the concentration of TNF-α, erythrocyte sedimentation rate or white blood cell counts in synovial tissue (51).

Of note, plasma BDNF levels decreased after 14 weeks of anti-TNF therapy. In spondyloarthritis (SPA), RA and osteoarthritis (OA), mRNA transcripts of all NTs and receptors were expressed in the inflamed synovium. At the protein level, BDNF was significantly higher in the synovial fluid of patients with SPA than in those with OA. Immunohistochemistry demonstrated that TrkA and NGF were highly expressed in the inflamed synovium of patients with SPA, correlating with vascularity and lymphoid aggregates. Additionally, the immunoreactivity of all receptors was significantly decreased after infliximab treatment (52,53).

BDNF in SLE

Recently, serum BDNF levels in SLE have been receiving increasing attention (54-59) and have been linked to various clinical parameters, suggesting the involvement of BDNF in the pathogenesis and progression of SLE. Fauchais et al (58) indicated that the serum levels of BDNF and the SLE disease activity index (SLEDAI) were not correlated.

Although BDNF levels were reduced after treatment, they remained higher in patients with SLE than in healthy controls. They speculated that BDNF levels were independent of the Th1 and Th2 profile. Furthermore, BDNF levels were the lowest in a subgroup of lupus anticoagulant-positive patients, which may have been due to antiphospholipid antibody-induced vascular lesions and oxidative stress, as in SSc (47). Ikenouchi et al (56) also reported that serum BDNF levels did not correlate with SLEDAI.

However, significantly increased BDNF levels exhibited a good correlation with psychiatric symptoms, including acute state of confusion, anxiety disorder, cognitive dysfunction, mood disorder and psychosis in neuropsychiatric syndrome of SLE (NPSLE). Ikenouchi-Sugita et al (54) and Ikenouchi et al (56) suggested that plasma BDNF levels and the catecholamine metabolites have a higher predictive value regarding the severity of psychotic symptoms in SLE, offering an alternate diagnosis to steroid-induced psychosis. Of note, Tamashiro et al (55) demonstrated that increased plasma BDNF levels did not correlate with CNS lesions, which contradicts previous studies.

In addition, they proved a negative correlation between plasma BDNF levels and SLEDAI and a positive correlation with the levels of complements and the numbers of circulatory lymphocytes. Zheng et al (59) suggested that decreased serum BDNF levels aggravated depression, while increased BDNF improved depression in SLE. The serum BDNF levels exhibited an increase in the stable stage of SLE and a decrease in the active stage. A study by our group indicated that the BDNF concentration decreased after repeated thawing of blood samples, suggesting poor stability of BDNF protein (9).

In this study, blood samples were collected during the same period for ELISA analysis within three months. However, in the study by Tamashiro et al (55), the blood samples of the control group were from the serum banks of clinical hospitals, which may have had lower BDNF protein levels due to degradation during long-term preservation. This notion is in agreement with the study by Zuccato et al (60), who also demonstrated a time-dependent change in serum BDNF levels due to different sample storage conditions.

The study by our group indicated that BDNF levels were correlated with the SLEDAI, levels of complements and the numbers of circulatory lymphocytes (9). In addition, it was demonstrated that serum BDNF levels in SLE were decreased and were the lowest in NPSLE. Another study suggested that plasma BDNF levels were consistently lower in patients with NPSLE with irreversible organic brain damage than in healthy controls and the level increased with the improvement in the disease (57). Thus, elevated BDNF levels may also be used to track the recovery of brain damage in NPSLE.

reference link : https://www.spandidos-publications.com/10.3892/etm.2021.10727


reference link :https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264557

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