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Page 292 Nociti. Neuroimmunol Neuroinflammation 2020;7:291-9 I http://dx.doi.org/10.20517/2347-8659.2020.25

neurological symptoms in most patients, with early clinical relapsing-remitting episodes and/or
[3]
radiological worsening and different degrees of recovery (RRMS) . The relapsing-remitting phase, in most
patients, is subsequently followed by a chronic progressive phase; approximately 10%-15% of patients show
a progressive form of the disease from onset.

For some authors, MS is an exclusive autoimmune inflammatory disease caused by dysregulated auto-
reactive immune cells that traverse the blood-brain barrier (BBB) into the CNS parenchyma, attacking
various cell types (the “outside-in” autoimmune hypothesis). For other authors it is a primary degenerative
disease (the “inside-out” hypothesis) in which inflammation is secondary to the release of auto-antigens
(components of myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein),
[4]
promoting autoimmunity . Thus far, it is difficult to discern whether the inflammatory processes of MS are
a product or a cause for neurodegeneration with a background autoimmune etiology. In all phases of the
disease both immune and degenerative processes appear to coexist and this makes it difficult to definitively
resolve the “outside-in” vs. “inside-out” controversy.

Despite this, there is well-documented evidence that, in MS, an uncontrolled inflammatory response in the
CNS (neuroinflammation) causes destruction through high levels of pro-inflammatory cytokines, proteases,
glutamate, and free radicals. Consequently, immunomodulatory drugs that reduce or suppress the activity
of immune cells have been successfully used to reduce clinical relapses in MS and/or neuroradiological
“activity”, which are associated with the entry of leukocytes through the BBB . Sustained disability,
[5]
however, is due to a progressive neurodegenerative process, ending with axonal loss and brain atrophy,
primary or secondary to the peripheral and compartmentalized inflammation in the CNS . To date, no
[6]
approved therapy has provided marked neuroprotective effects nor have commonly anti-inflammatory
therapies, used in the treatment of the disease, showed great efficacy in the progressive phase of MS.

Neuroinflammation have not only harmful but also neuroprotective effects [7,8] . In MS and other
[9]
neurological diseases, the reparative activities of inflammatory response have been demonstrated .
Therefore, some authors introduced the concept of “neuroprotective autoimmunity” [10,11] . The release of
neurotrophins by immune cells in both peripheral blood and directly into inflammatory lesions in MS [12,13] ,
but also by microglia and astrocytes in the CNS, stimulating neuronal growth and survival, seems to be a
[14]
possible mechanism for this neuroprotective effect . Among neurotrophins, brain derived neurotrophic
factor (BDNF) seems to be a good candidate in promoting the beneficial effects of inflammation in MS.

In this review, the role of BDNF in MS neuroinflammation and as a novel therapeutic target will be
discussed.

NEUROINFLAMMATION: THE DETRIMENTAL EFFECT
MS pathophysiology is characterized by altered bidirectional interactions between several immune cell
types in the periphery and resident cells of the CNS, such as microglia and astrocytes . The MS relapses,
[15]
typical in the early phases of disease, are characterized by the infiltration of pro inflammatory CNS-
specific effector T cells (CD4+ and CD8+ T cells), B cells and myeloid cells into the CNS parenchyma,
[16]
that are activated and/or regulated in an aberrantly way . The altered function of regulatory T (Treg)
cells and resistance of CNS-specific effector T cells to Treg cell-mediated regulation could be a possible
cause of the neuroinflammation [17-21] . Furthermore, CNS-resident cells, that secrete many inflammatory
mediators, recruit inflammatory cells into the CNS. Microglia and astrocytes in particular, can also produce
cytokines, chemokines and reactive oxygen species in the presence of homeostatic disturbance, promoting
and sustaining axonal damage and neurodegeneration in MS . Therefore, both peripheral and CNS-
[16]
[22]
compartmentalized inflammatory mechanisms contribute to MS pathogenesis .