**2. Neuroprotective effects of disease modifying drugs (DMDs)**

Recently, significant advances in MS therapy have been made, but these advances have been

Understanding of endogenous defense activity (**Figure 1**), including neurotrophicity, neuro‐ protection, neuroplasticity, neurogenesis, and remyelination, is essential for pharmacological neuroprotection and enhanced neurorecovery. Neurotrophicity includes the processes necessary for the maintenance of a normal phenotype. Neuroprotection is the sum of all processes aimed at counterbalancing the pathophysiological mechanisms that are induced by the alteration of neuro-immune responses. Neuroplasticity represents the sum of the structural and functional changes that must occur for adaptation to new internal or environmental stimuli. Neurogenesis, in a broad sense, refers to the capacity of brain tissue to generate new neurons, astrocytes, and oligodendrocytes [1]. Remyelination is a physiological regenerative process that requires the activation of oligodendrocyte precursor cells (OPCs), their migration, recruitment, and differentiation into remyelinating oligodendrocytes and their interaction with denuded axons. Changes in these steps, which are characteristic of MS, promote neuro‐

limited to the prevention of relapse, and long-term results are conflicting.

degeneration.

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**Figure 1.** Endogenous defense activity and damage mechanism.

Classical neuroprotection approaches include the use of the already Food and Drug Admin‐ istration (FDA)-approved disease modifying drugs (DMDs) and a wide spectrum of pharma‐ cological compounds that interact with one or more pathological processes (inflammation, Several DMDs are currently approved by the FDA for MS: interferons (interferon beta 1b or IFNB-1b, interferon beta-1a or IFNB-1a), glatiramer acetate (GA), traditional immunosuppres‐ sants (mitoxantrone), fingolimod, and monoclonal antibodies (natalizumab, alemtuzumab, and daclizumab) as well as the recently approved drugs teriflunomide and dimethyl fumarate (DMF). The main target of these molecules is the modulation of immune mechanisms and inflammation, along with a debatable effect on disease progression. **Table 1** summarizes the available information about FDA-approved DMDs, including their mechanisms of action and severe adverse effects [**Table 1**]. The neuroprotective effects of these agents against neurode‐ generation and their ability to promote reparative processes are still under investigation.




**FDAapproved DMDs**

Peg interferon beta-1a (Plegridy)

Glatiramer acetate (Copaxone)

//5Interferon beta-1a (Avonex; Rebif)

**Indication Primary**

First line therapy for RR-MS, SP-MS, and CIS (only Avonex)

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First-line therapy for RR-MS

First-line therapy for RR-MS and CIS

**mechanisms of action**

Suppresses the proliferation of MBP-specific T

Suppresses the proliferation of MBP-specific T cells. Inhibits the secretion of proinflamma-tory cytokines

Suppresses the proliferation of MBP-specific T

cells. Shifts the population of T cells from proinflammatory Th1 cells to regulatory Th2

cells

cells. Inhibits the secretion of pro-inflammatory cytokines

**Neuroprotective effects—results from basic research studies**

Anti-inflammatory, antioxidative, and anti-apoptotic effects [10, 11]. Increased BDNF and IGF-2 Proremyelination and proregenerative proprieties [12, 13]

**Neuroprotective effects—results from clinical research studies**

– – Hepatotoxicity,

– – Hepatotoxicity,

Conflicting results: there found both increased and no effect upon serum BDNF levels [14–16]. Imaging data supports the neuroprotective and pro-myelinating properties of GA by showing that patients treated with GA are less

likely

to develop "black holes" than nontreated patients and have demonstrated a significant increase in the NAA–Cr ratio compared to pre-treatment values **Severe adverse effects**

congestive heart failure, seizures, depression or suicidal thoughts

congestive heart failure, seizures, depression or suicidal thoughts

Injection site lipoatrophy and necrosis, panic disorder, bowel disorder


Abbreviations: LTi―lymphoid tissue inducer; IGF-2—insulin growth factor; MPB—myelin-basic protein; BDNF―brain-derived neurotrophic factor; GDNF—glial cell-derived nerve factor; Nrf2—nuclear factor erythroid 2 related factor; BBB—blood–brain barrier, RR-MS―relapse remitting MS; SP-MM—secondary progressive MS, CIS clinical-isolated syndrome; PML—progressive multifocal leukoencephalopathy; LTi—lymphoid tissue inducer.

**Table 1.** The neuroprotective effects of FDA-approved DMD.

In addition to the currently FDA-approved DMDs, some promising new agents are already in ongoing late-phase clinical trials, such as laquinomid, ozanimod, ponesimod, siponimod, ocrelizumab, ofatumumab, masitinib, and cladribine. Few data related to the mechanisms of action of these drugs are currently available. Of these compounds, laquinimod is the only one that appears to have neuroprotective properties, and laquinimod is currently being tested in patients with RR-MS in a third phase III trial, CONCERTO [23]. Basic research studies suggest that in addition to its neuromodulatory and anti-inflammatory effects, laquinimod also displays neuroprotective effects through several mechanisms, including reducing excitotox‐ icity, increasing serum levels of BDNF, downregulating the astrocytic pro-inflammatory response, reducing astrocytic nuclear factor κB (NFκB) activity, and preserving cannabinoid receptor type 1 expression [24]. However, to date, the results of phase II and III clinical trials have failed to show a clear effect of laquinimod in RR-MS patients [25, 26].
