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binding of BDNF to the TrkB receptor can also induce the expression of NF-κB but, the pathways for this
[54]
modulation are not yet completely understood . Thus, the role of BDNF in neuroinflammation, is strongly
linked to its ability to induce, and being induced by, NF-κB.

[56]
Lai et al. recently demonstrated that BDNF modulates inflammatory homeostasis, reducing inflammatory
activity on microglia also through the erythropoietin and sonic hedgehog signalling pathways. BDNF may
also influence the microglia inflammatory response differently in male and females probably by driving
[57]
activated microglia responses toward a less inflammatory pattern in females .

The understanding of BDNF function in humans has greatly benefited from the identification of an SNP in
the BDNF gene that causes a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met, c.196G>A,
dbSNP: rs6265). In this Met variant form of BDNF carriers, that is, BDNF Val/Met heterozygotes and Met/
[58]
Met homozygotes, the pro-domain structure of the gene is altered . The polymorphism can potentially
alter BDNF protein-protein interactions, binding affinities, localisation, or conformational stability of the
protein. Whether the polymorphism has any significant impact on the proteome profile or posttranslational
modifications of various proteins in the neuronal tissues or body fluids is currently unknown . Several
[58]
studies have emerged implicating the association or otherwise of this polymorphism with MS. So far, no
conclusive data have been published . New advances in the epigenetic field, highlight the role of BDNF
[59]
antisense RNA (BDNF-AS), a naturally conserved long noncoding RNA, and of DNA methylation, in the
regulation of BDNF expression in MS and in several neurological diseases [60-63] . So far, only few studies have
[64]
been published on this argument .

BDNF in MS
BDNF is the neurotrophin which is expressed more in inflammatory brain lesions of MS patients [12,13] . A
significant amount of BDNF was found in infiltrating immune cells, overall in T cells and macrophages,
[11]
and in neurons and astrocytes . BDNF is expressed by immune cells in actively demyelinating areas of
MS lesions but not in lesions without ongoing myelin breakdown. Moreover, the neurotrophin is expressed
more in the actively demyelinating edge of the plaque in the early phase of its development. It is released
near to axons, not directly attacked by activated immune system cells but is at high risk of bystander
[13]
damage . Outside MS lesions, neurons are the major source of BDNF . The literature data agree in
[13]
showing that neurons are the major targets for neurotrophic interactions in the CNS. In particular, the
full-length isoforms of TrkB (receptor for BDNF and NT4/5) and TrkC (receptor for NT3) are usually
expressed on neuronal cells. Neurons close to MS plaques showed a prominent expression of full-length
[11]
TrkB (gp145TrkB) . Moreover, TrkB is upregulated in a part of damaged neurons. It is known that BDNF
can be anterogradely transported and released by neurons. This process is up-regulated after axonal injury
[65]
and transection . The common occurrence of axonal damage in MS suggests that neuronal BDNF might
contribute to endogenous neurotrophic support in MS plaques [66,67] .

[13]
In older and chronic MS plaques, endogenous neurotrophins are low . This may be one cause for the
ongoing axonal degeneration in the chronic progressive stage of MS [68-70] .

In the relapsing phase, levels of BDNF are generally reported to be increased in peripheral blood
[73]
mononuclear cells (PBMC) and serum [71,72] , but Azoulay et al. found less BDNF in the serum of RRMS
patients with no difference in remission and relapse phases. In MS patients, serum and CSF levels and
PBMC secretion of BDNF are reduced compared to healthy controls [74,75] . In line with neuropathological
findings [68-70] , BDNF production by immune cells in RRMS patients is higher compared to progressive
MS, suggesting again that progression of MS may be due to a failure of neuroprotection and neurorepair
functions under chronic injury [72,75] .