Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity.

Emerging evidence suggests that immunological mechanisms underlie metabolic control of adipose tissue. Here, we have shown the regulatory impact of a rare subpopulation of dendritic cells, rich in perforin-containing granules (perf-DCs). Using bone marrow transplantation to generate animals selectively lacking perf-DCs, we found that these chimeras progressively gained weight and exhibited features of metabolic syndrome. This phenotype was associated with an altered repertoire of T cells residing in adipose tissue and could be completely prevented by T cell depletion in vivo. A similar impact of perf-DCs on inflammatory T cells was also found in a well-defined model of multiple sclerosis, experimental autoimmune encephlalomyelitis (EAE). Thus, perf-DCs probably represent a regulatory cell subpopulation critical for protection from metabolic syndrome and autoimmunity.

Astrocytes in Multiple Sclerosis-Essential Constituents with Diverse Multifaceted Functions.

In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties.

Neuroprotective Effect of Glatiramer Acetate on Neurofilament Light Chain Leakage and Glutamate Excess in an Animal Model of Multiple Sclerosis.

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35-55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.

Glatiramer Acetate: from Bench to Bed and Back.

BACKGROUND: Glatiramer acetate (GA, Copaxone®, Copolymer1, Cop 1) is an approved drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy in reducing the frequency of exacerbations and its safety profile establish it as a first-line therapy for MS. Evidence from the animal model experimental autoimmune encephalomyelitis (EAE) and from MS patients indicate that GA affects various levels of the innate and the adaptive immune response, inducing deviation from the pro-inflammatory to the anti-inflammatory pathways. This includes mainly the induction of Th2/3 and T-regulatory cells, and down-regulation of both Th1 and Th17 cells. The immune cells induced by GA reach the CNS and secrete in situ anti-inflammatory cytokines, alleviating the pathological processes. In addition to its immunomodulatory activities, GA promotes neuroprotective repair processes such as secretion of neurotrophic factors, remyelination and neurogenesis, indicating that repair process in the CNS can be up-regulated by therapy.

Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis.

To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood-brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin-5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses. Furthermore, examination of individual astrocytic processes at cortical layer IV, where well-defined neuronal columns (barrels) are linked to functional properties, revealed loss of astrocytic confinement to the functional neuronal boundaries. Thus, in contrast to the highly modulated patches of astrocyte processes in naïve mice overlapping the barrel cores, in EAE-mice process distribution was uniform ignoring the barrel boundaries. These aberrations are attributed to the surrounding inflammation, indicated by T-cells presence in the cortex as well as in the subcortical white matter and the meninges. Immunomodulatory treatment with glatiramer acetate partially abrogated the neurovascular damage. These combined findings indicate that under inflammatory conditions, activated perivascular astrocytes fail in neuro-hemodynamic coupling, resulting in obstructed cross-talk between the blood vessels and the neurons. We propose that loss of cortical astrocytic regulation and fine-tuning between the blood supply and the neuronal needs contributes to the neurological impairment and cognitive decline occurring in EAE/MS as well as to the disease progression.

Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis.

In demyelinating diseases such as multiple sclerosis, disrupted myelin structures impair the functional role of the sheath as an insulating layer for proper nerve conduction. Though the etiology and recovery pathways remain unclear, in vivo studies show alterations in the lipid and the adhesive protein (myelin basic protein, MBP) composition. We find that in vitro cytoplasmic myelin membranes with modified lipid composition and low MBP concentration, as in demyelinating disease, show structural instabilities and pathological phase transition from a lamellar to inverted hexagonal, which involve enhanced local curvature. Similar curvatures are also found in vivo in diseased myelin sheaths. In addition, MBP dimers form a correlated mesh-like network within the inner membrane space, only in the vicinity of native lipid composition. These findings delineate the distinct functional roles of dominant constituents in cytoplasmic myelin sheaths, and shed new light on mechanisms disrupting lipid-protein complexes in the diseased state.

Epitope mapping of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a mouse model of multiple sclerosis: microwave-assisted synthesis of the peptide antigens and ELISA screening.

The role of pathologic auto-antibodies against myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is a highly controversial matter. As the use of animal models may enable to unravel the molecular mechanisms of the human disorder, numerous studies on multiple sclerosis are carried out using experimental autoimmune encephalomyelitis (EAE). In particular, the most extensively used EAE model is obtained by immunizing C57BL/6 mice with the immunodominant peptide MOG(35-55). In this scenario, we analyzed the anti-MOG antibody response in this model using the recombinant refolded extracellular domain of the protein, MOG(1-117). To assess the presence of a B-cell intramolecular epitope spreading mechanism, we tested also five synthetic peptides mapping the 1-117 sequence of MOG, including MOG(35-55). For this purpose, we cloned, expressed in Escherichia coli and on-column refolded MOG(1-117), and we applied an optimized microwave-assisted solid-phase synthetic strategy to obtain the designed peptide sequences. Subsequently, we set up a solid-phase immunoenzymatic assay testing both naïve and EAE mice sera and using MOG protein and peptides as antigenic probes. The results obtained disclose an intense IgG antibody response against both the recombinant protein and the immunizing peptide, while no response was observed against the other synthetic fragments, thus excluding the presence of an intramolecular epitope spreading mechanism. Furthermore, as the properly refolded recombinant probe is able to bind antibodies with greater efficiency compared with MOG(35-55), we hypothesize the presence of both linear and conformational epitopes on MOG(35-55) sequence.

Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis.

IFNß is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNß. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via "PASylation." PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35-55-induced experimental autoimmune encephalomyelitis compared with IFNß, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b(+)/CD45(hi) myeloid lineage cells detectable in the CNS, as well as a decrease in IBA(+) cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4(+) cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease.

Chromatin conformation governs T-cell receptor Jß gene segment usage.

T cells play fundamental roles in adaptive immunity, relying on a diverse repertoire of T-cell receptor (TCR) α and ß chains. Diversity of the TCR ß chain is generated in part by a random yet intrinsically biased combinatorial rearrangement of variable (Vß), diversity (Dß), and joining (Jß) gene segments. The mechanisms that determine biases in gene segment use remain unclear. Here we show, using a high-throughput TCR sequencing approach, that a physical model of chromatin conformation at the DJß genomic locus explains more than 80% of the biases in Jß use that we measured in murine T cells. This model also predicts correctly how differences in intersegment genomic distances between humans and mice translate into differences in Jß bias between TCR repertoires of these two species. As a consequence of these structural and other biases, TCR sequences are produced with different a priori frequencies, thus affecting their probability of becoming public TCRs that are shared among individuals. Surprisingly, we find that many more TCR sequences are shared among all five mice we studied than among only subgroups of three or four mice. We derive a necessary mathematical condition explaining this finding, which indicates that the TCR repertoire contains a core set of receptor sequences that are highly abundant among individuals, if their a priori probability of being produced by the recombination process is higher than a defined threshold. Our results provide evidence for an expanded role of chromatin conformation in VDJ rearrangement, from control of gene accessibility to precise determination of gene segment use.

Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate.

Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g-ratios, in spinal cords of GA-injected mice compared with their PBS-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA-injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination.

Immunomodulation neuroprotection and remyelination - the fundamental therapeutic effects of glatiramer acetate: a critical review.

Multiple sclerosis (MS) is a multifaceted heterogeneous disease with various patterns of tissue damage. In addition to inflammation and demyelination, widespread axonal and neuronal pathologies are central components of this disease. MS therapies aim to restrain the pathological processes, enhance protective mechanisms, and prevent disease progression. The amino acid copolymer, glatiramer acetate (GA, Copaxone), an approved treatment for MS, has a unique mode of action. Evidence from the animal model experimental autoimmune encephalomyelitis (EAE) and from MS patients indicates that GA affects various levels of the innate and the adaptive immune response, inducing deviation from the pro-inflammatory to the anti-inflammatory pathways. This includes competition for the binding of antigen presenting cells, driving dendritic cells, monocytes, and B-cells towards anti-inflammatory responses, induction of Th2/3 and T-regulatory cells, and downregulating of both Th1 and Th-17 cells. The immune cells induced by GA reach the inflamed disease organ and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings have revealed that in addition to its immunomodulatory activities GA promotes neuroprotective repair processes such as neurotrophic factors secretion and remyelination. This review aims to provide a comprehensive overview on the diverse mechanism of action of GA in EAE/MS, in particular on the in situ effect of GA and its ability to generate neuroprotection and repair in the CNS. In view of its immunomodulatory activity, the beneficial effects of GA in various models of additional autoimmune related pathologies, such as immune rejection and inflammatory bowel disease (IBD), are also presented.

Role of Helical Structure in MBP Immunodominant Peptides for Efficient IgM Antibody Recognition in Multiple Sclerosis.

The involvement of Myelin Basic Protein (MBP) in Multiple Sclerosis (MS) has been widely discussed in the literature. This intrinsically disordered protein has an interesting α-helix motif, which can be considered as a conformational epitope. In this work we investigate the importance of the helical structure in antibody recognition by MBP peptides of different lengths. Firstly, we synthesized the peptide MBP (81-106) (1) and observed that its elongation at both N- and C-termini, to obtain the peptide MBP (76-116) (2) improves IgM antibody recognition in SP-ELISA, but destabilizes the helical structure. Conversely, in competitive ELISA, MBP (81-106) (1) is recognized more efficiently by IgM antibodies than MBP (76-116) (2), possibly thanks to its more stable helical structure observed in CD and NMR conformational experiments. These results are discussed in terms of different performances of peptide antigens in the two ELISA formats tested.

Beneficial effect of glatiramer acetate treatment on syndecan-1 expression in dextran sodium sulfate colitis.

Syndecan-1, the most abundant heparan sulfate proteoglycan in the gastrointestinal tract, is reduced in the regenerative epithelium in inflammatory bowel disease (IBD). This study explored the effects of the immunomodulator glatiramer acetate (GA; Copaxone) treatment on syndecan-1 expression in dextran sodium sulfate (DSS)-induced colitis. Acute and chronic colitis was induced in C57BL/6 mice by 2 and 1.5% DSS in tap water, respectively. GA was applied subcutaneously, 2 mg per mouse per day, starting on the day of DSS induction until the mice were sacrificed. Syndecan-1 expression was assessed by immunohistochemistry. The effect of adoptive transfer of GA-specific T cells as an organ-specific therapy also was evaluated. Syndecan-1 expression was significantly lower in both colitis groups compared with that in naive mice (p < 0.0001). GA attenuated clinical scores and pathological manifestations of colitis and led to the reinstatement of normal levels of syndecan-1. After adoptive transfer, GA-specific cells homed to the surface epithelium of the distal colon, accompanied by the augmentation of syndecan-1 staining in their vicinity. We concluded that syndecan-1 expression is reduced in DSS-induced colitis and could be a potential prognostic factor in IBD. Treatment with GA exerts not only an anti-inflammatory effect but also a possible beneficial effect in stabilizing the intestinal epithelium barrier and tissue repair in DSS colitis. GA may be applied as a novel drug for IBD, shifting treatment from immunosuppression toward immunomodulation.

Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate.

The respective roles of inflammatory and neurodegenerative processes in the pathology of multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. Novel treatment strategies aim to operate within the CNS to induce neuroprotection and repair processes in addition to their anti-inflammatory properties. In this study we analyzed and compared the in situ pathological manifestations of EAE utilizing two different models, namely the relapsing-remitting PLP-induced and the chronic MOG-induced diseases. To characterize pathological changes, both transmission electron microscopy (TEM) and immunohistochemistry were employed. The effect of the approved MS drug glatiramer acetate (GA, Copaxone) on myelin damage/repair and on motor neuron loss/preservation was studied in both EAE models. Ultrastructural spinal cord analysis revealed multiple white matter damage foci, with different patterns in the two EAE models. Thus, the relapsing-remitting model was characterized mainly by widespread myelin damage and by remyelinating fibers, whereas in the chronic model axonal degeneration was more prevalent. Loss of lower motor neurons was manifested only in mice with chronic MOG-induced disease. In the GA-treated mice, smaller lesions, increased axonal density and higher prevalence of normal appearing axons were observed, as well as decreased demyelination and degeneration. Furthermore, quantitative analysis of the relative remyelination versus demyelination, provides for the first time evidence of significant augmentation of remyelination after GA treatment. The loss of motor neurons in GA-treated mice was also reduced in comparison to that of EAE untreated mice. These effects were obtained even when GA treatment was applied in a therapeutic schedule, namely after the appearance of clinical symptoms. Hence, the remyelination and neuronal preservation induced by GA are in support of the neuroprotective consequences of this treatment.

Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis.

The interplay between demyelination and remyelination is critical in the progress of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In the present study, we explored the capacity of glatiramer acetate (GA, Copaxone) to affect the demyelination process and/or lead to remyelination in mice inflicted by chronic EAE, using both scanning electron microscopy and immunohistological methods. Spinal cords of untreated EAE mice revealed substantial demyelination accompanied by tissue destruction and axonal loss. In contrast, in spinal cords of GA-treated mice, in which treatment started concomitantly with disease induction (prevention), no pathology was observed. Moreover, when treatment was initiated after the appearance of clinical symptoms (suppression) or even in the chronic disease phase (delayed suppression) when substantial demyelination was already manifested, it resulted in a significant decrease in the pathological damage. Detection of oligodendrocyte progenitor cells (OPCs) expressing the NG2 or O4 markers via colocalization with the proliferation marker BrdU indicated their elevated levels in spinal cords of GA-treated mice. The mode of action of GA in this system is attributed to increased proliferation, differentiation, and survival of OPCs along the oligodendroglial maturation cascade and their recruitment into injury sites, thus enhancing repair processes in situ.

Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, is a widely used multiple sclerosis (MS) model. Unlike the spontaneous occurrence of MS, in EAE, external immunization with the MOG peptide (200-300 µg/mouse), emulsified in adjuvant enriched with Mycobacterium Tuberculosis (MT) H37Ra (100-500 µg mouse), and pertussis toxin (PTx, 200-500 ng/mouse) injections, are applied, which heavily boosts the immune system. NEW METHOD: A detailed and systematic titration of the MOG 35-55 EAE induction protocol in C57BL/6 mice reveals the minimal doses of the MOG 35-55 peptide, MT H37Ra, and PTx, required for disease manifestation. RESULTS: The amounts of MOG 35-55 peptide, MT H37Ra, and PTx can be drastically reduced from the standard protocol, to level of 5 µg MOG, 25 µg MT H37Ra, and 50 ng PTx, without affecting the clinical manifestations. The titrated protocols induced a high disease incidence and a consistent robust disease course, with full histopathological characteristics of the MOG model, inflammation, demyelination and axonal damage. COMPARISON WITH EXISTING METHODS: Similar disease incidences, day of symptoms appearance, maximal clinical score, and histopathology were obtained for the standard and the titrated protocols. CONCLUSIONS: Reducing the reagent dosages used for EAE induction, without attenuating the disease, can give a truer and less artificial perspective of MS. We propose an improved protocol for this extensively used model, with high disease incidence, a consistent robust course, and characteristic histological manifestations, which may be more sensitive for testing therapeutic modalities, cost-effective, and less distressing to the animals.

The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5.

B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

Glatiramer acetate increases T- and B -regulatory cells and decreases granulocyte-macrophage colony-stimulating factor (GM-CSF) in an animal model of multiple sclerosis.

To identify the mechanisms relevant for the therapeutic effect of glatiramer acetate (GA), we studied T- and B- regulatory cells as well as GM-CSF expression in mice recovered from experimental autoimmune encephalomyelitis (EAE). Selective depletion of Tregs reduced but did not eliminate the ability of GA to ameliorate EAE, indicating a role for additional immune-subsets. The prevalence of Bregs in the periphery and the CNS of EAE-mice increased following GA-treatment. Furthermore, GA downregulated the pathological expression of GM-CSF, on both the protein and mRNA levels. These findings corroborate the broad immunomodulatory mechanism of action of GA in EAE/MS.

Neuroprotection and neurogeneration in MS and its animal model EAE effected by glatiramer acetate.

It is by now established that multiple sclerosis (MS) is not simply an autoimmune disease and that in addition to inflammation and demyelination, axonal injury and neuronal loss underlie the accumulation of disability and the disease progression. Specific treatment strategies should thus target the injury sites at the central nervous system (CNS) to interfere with both neuroinflammation and neurodegeneration. Glatiramer acetate (GA Copaxone, Copolymer 1), an approved drug for the treatment of multiple sclerosis, was shown earlier to act as an anti-inflammatory and immunomodulatory agent. In this mini-review its effect on neuroprotection, neurogenesis and on the remyelination process is delineated in the EAE model. The plausible mechanism underlying this multifactorial effect is the induction of GA-reactive T-cells in the periphery and their infiltration into the CNS, where they release immunomodulatory cytokines and neurotrophic factors in the injury site, suggesting a direct linkage to its therapeutic effect in both EAE and MS.

Linkage between immunomodulation, neuroprotection and neurogenesis.

Neuronal protection and restoration are the major goals for the therapy of neurodegenerative diseases, representing a very active field of research. In multiple sclerosis, treatments need to target both the autoimmune inflammation and the pathological neurodegeneration. The optimal therapeutic approach may promote remyelination and axonal repair, and even lead to neuronal renewal. This review article will discuss both endogenous neuroprotective mechanisms and those triggered by potential therapies. Currently employed immunomodulatory treatments and their ability to induce neuroprotection, tissue repair and neurogenesis are also presented.