The Role of BDNF in Multiple Sclerosis Neuroinflammation

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed.

Keywords: CNS inflammation; MS; brain-derived neurotrophic factor; demyelinating diseases; neuroprotection; neurotrophin.

Figure 1

Production of brain-derived neurotrophic factor (BDNF). The synthesis and folding of the BDNF protein in a precursor form called pre-pro-BDNF occur in the endoplasmic reticulum. The pre-region sequence of the precursor is then cleaved, resulting in the production of the pro-neurotrophin isoform of BDNF (pro-BDNF). Following cleavage of the pro-domain sequence, pro-BDNF is then converted into the mature isoform (m-BDNF). Both pro-BDNF and m-BDNF isoforms are released into the extracellular space, where pro-BDNF can be converted by metalloproteinases 2 (MMP2) and 9 (MMP9), plasmin, and extracellular proteases. BDNF, brain-derived neurotrophic factor; m-BDNF, the mature isoform of BDNF; MMP2, metalloprotease 2; MMP9, metalloprotease 9; pre-pro-BDNF, the uncleaved precursor form of BDNF; pro-BDNF, the pro-neurotrophin isoform of BDNF.

Figure 2

The binding of the mature BDNF isoform (m-BDNF) to the tyrosine kinase B (TrkB) receptor leads to dimerization and phosphorylations in the intracellular Trk domains, thereby initiating the cytoplasmic signaling pathways mediated by activation of the phosphatidylinositol 3-kinase (PI3K), the mitogen-activated protein kinase (MAPK), and phospholipase C (PLC). Ultimately, the activation of these pathways leads to dendritic growth and branching, as well as regulation of apoptosis and synaptic plasticity. The binding of the pro-neurotrophin isoform of BDNF (pro-BDNF) to the p75 neurotrophin receptor (p75NTR) leads to the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, which promotes apoptosis, and the RhoA (Ras homolog gene family member) and nuclear factor kappa B (NF-ĸB) signaling pathways, which cause neuronal growth and neuronal survival. Akt, protein kinase B; BDNF, brain-derived neurotrophic factor; DAG, diacylglycerol; ERK, extracellular signal-regulated kinases; IP3, inositol trisphosphate 3; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; NF-ĸB, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase; PCK, protein kinase C; PLC, phospholipase C; RhoA, Ras homolog gene family member; TrkB, tyrosine kinase B.

Figure 3

Brain-derived neurotrophic factor (BDNF) influences the endogenous cross-talk between astrocytes and microglia in modulating neuroinflammatory mechanisms. BDNF plays an important role in the regulation of the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes. BDNF, brain-derived neurotrophic factor; OPC, oligodendrocyte precursor cells.