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Page 296 Nociti. Neuroimmunol Neuroinflammation 2020;7:291-9 I http://dx.doi.org/10.20517/2347-8659.2020.25

Numerous studies tried to correlate the role of rs6265 BDNF polymorphism with the prognosis of MS
patients, with conflicting data so that other mechanisms could be involved in the modulation of BDNF
[59]
gene . Latest advances in the field of epigenetics highlight the role of epigenetic mechanisms, such as
methylation, in controlling key biological processes. The presence of rs6265 SNP is not a prognostic factor
[64]
for reaching a more severe Expanded Disability Status Scale (EDSS) . When the percentage of methylation
of the BDNF gene is considered, a lower percentage is associated with higher odds in achieving significant
disability regardless of its polymorphism. Being a higher methylation a “silencer” of the gene, a lower
inhibition of the gene correlates with a high probability in achieving an EDSS score of 6.0. Patients with
more severe inflammation could appeal to a de-methylation to have a higher secretion of BDNF, preserving
better CNS functions. The same patients tend to reach a more severe disability score by depleting the
[64]
functional reserves of the brain at a faster rate . If BDNF methylation is considered as an epiphenomenon
of the disease activity (or better of the neuroinflammation status), it might help to differentiate patients
with a higher degree of inflammation from patients with a lower ones. If these data will be confirmed by
other studies, BDNF rs6265 polymorphism methylation could become a valid prognostic factor in MS to
[64]
precociously recognise patients with a more severe disease from those with a milder one .

BDNF AS PROMISING THERAPY IN MS
MS, but also many other CNS diseases, are tricky to treat due to the difficulty of drugs to cross the BBB. To
do this, a drug must have the appropriate physicochemical properties. Alternatively, some drugs may be
directly injected into the CNS but these invasive procedures are not risk-free.

Most available MS treatment have an exclusive anti-inflammatory effect helpful in reducing clinical
and neuroradiological relapses but ineffective in preventing axonal loss and neurodegeneration. On the
other hand, neuroprotective and/or remyelinating molecules failed to achieve the primary endpoint in
clinical trials [76,77] . Conversely, brain delivery of BDNF has a potential role in reversing neurodegenerative
diseases [78,79] but, so far, not through systemic administration. Therefore, there is an urgent need for
development of a non-invasive trans-BBB delivery method. All the therapeutic strategies designed for
[80]
delivery of neurotrophins are well summarised in the review by Huang and Dreyfus .
Recently, the possibility to deliver BDNF in a non-invasive way into the CNS through a BBB modulator,
[81]
the ADTC5, has been found . BDNF + ADTC5 delivered to the brains of mice with RR-EAE via systemic
administration, significantly improve the clinical body scores of EAE mice and induce remyelination,
compared to controls. Further studies are needed to confirm these data and to definitively find the best way
to delivery BDNF in CNS via systemic administration.

CONCLUSION
Few studies investigated the link between BDNF and neuroinflammation even if, in many brain disorders,
neuroinflammation and altered BDNF expression are commonly found. Better understanding of the
interaction between BDNF and neuroinflammation could help in improving the knowledge of diseases
pathogenesis and in developing of new therapeutic strategies for CNS disorders.

In MS, a large body of neuropathological, experimental and clinical evidences shows that BDNF may play
an important role in neuroinflammation modulation, neuroprotection and neurorepair. These data make
BDNF a good candidate for new therapeutic strategies in MS. But, when growth factors are considered
as possible treatments in brain disease, some issues have to be taken into account: first, how to increase
growth factors levels within specific regions of the CNS; second, how to optimize entry of growth factors
from the periphery; third, to define the rate at which BDNF is taken up by the brain; fourth, the need to
better understand the pharmacological characteristics of BDNF-based substances. Further studies are
needed to define these aspects.