The role of growth factors as a therapeutic approach to demyelinating disease

Huang, Yeen; Dreyfus, Cheryl F.

doi:10.1016/j.expneurol.2016.02.023

Cited by 42 publications

(40 citation statements)

References 198 publications

(217 reference statements)

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“…Systemic FAK inhibition in β-gal CNTF reporter heterozygous mice, had increased CNTF expression in areas neighboring the SVZ, including striatum and the white matter of the corpus callosum, and overlying cortex. This may be relevant to rescuing striatal neurons in Huntington's disease and oligodendrocytes in multiple sclerosis, respectively, given CNTF's trophic effects in animal models (Huang & Dreyfus, 2016;Ramaswamy & Kordower, 2012). Our data suggest that promoting neurogenesis requires increased CNTF without concomitant increases in LIF and/or IL-6, which are known to reduce neuroblast formation by promoting stem cell selfrenewal (Bauer & Patterson, 2006;Bowen et al, 2011;Covey et al, 2011;Gregg & Weiss, 2005;Pitman et al, 2004;Shimazaki et al, 2001).…”

Section: Fak-jnk Pathway Inhibition Uniquely Increases Cntf Expressmentioning

confidence: 71%

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Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Jia

Keasey

Lovins

et al. 2018

Glia

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Astrocyte-derived ciliary neurotrophic factor (CNTF) promotes adult subventricular zone (SVZ) neurogenesis. We found that focal adhesion kinase (FAK) and JNK, but not ERK or P38, repress CNTF in vitro. Here, we defined the FAK-JNK pathway and its regulation of CNTF in mice, and the related leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), which promote stem cell renewal at the expense of neurogenesis. Intrastriatal injection of FAK inhibitor, FAK14, in adult male C57BL/6 mice reduced pJNK and increased CNTF expression in the SVZ-containing periventricular region. Injection of a JNK inhibitor increased CNTF without affecting LIF and IL-6, and increased SVZ proliferation and neuroblast formation. The JNK inhibitor had no effect in CNTF−/− mice, suggesting that JNK inhibits SVZ neurogenesis by repressing CNTF. Inducible deletion of FAK in astrocytes increased SVZ CNTF and neurogenesis, but not LIF and IL-6. Intrastriatal injection of inhibitors suggested that P38 reduces LIF and IL-6 expression, whereas ERK induces CNTF and LIF. Intrastriatal FAK inhibition increased LIF, possibly through ERK, and IL-6 through another pathway that does not involve P38. Systemic injection of FAK14 also inhibited JNK while increasing CNTF, but did not affect P38 and ERK activation, or LIF and IL-6 expression. Importantly, systemic FAK14 increased SVZ neurogenesis in wildtype C57BL/6 and CNTF+/+ mice, but not in CNTF−/− littermates, indicating that it acts by upregulating CNTF. These data show a surprising differential regulation of related cytokines and identify the FAK-JNK-CNTF pathway as a specific target in astrocytes to promote neurogenesis and possibly neuroprotection in neurological disorders.

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Section: Fak-jnk Pathway Inhibition Uniquely Increases Cntf Expressmentioning

confidence: 71%

“…This may be relevant to rescuing striatal neurons in Huntington’s disease and oligodendrocytes in multiple sclerosis, respectively, given CNTF’s trophic effects in animal models (Huang and Dreyfus 2016; Ramaswamy and Kordower 2012). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Jia

Keasey

Lovins

et al. 2018

Glia

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“…FGF‐2 is a mediator of adult neurogenesis and described in the literature to be involved in the recruitment of OPCs (Watts et al, ). Recent research showed that FGF‐2 is highly expressed by active astrocytes in the subventricular zone in the adult brain, enhances the recruitment of progenitor cells, and therefore facilitates myelin repair (Azin, Mirnajafi‐Zadeh, & Javan, ; Huang & Dreyfus, ). In experimental demyelination, FGF‐2 mRNA levels peaked at the initial stage of remyelination supporting a remyelination‐enhancing role (Messersmith, Murtie, Le, Frost, & Armstrong, ).…”

Section: Discussionmentioning

confidence: 99%

The formation of a glial scar does not prohibit remyelination in an animal model of multiple sclerosis

Haindl

Köck

Zeitelhofer-Adzemovic

et al. 2018

Glia

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The role of astrocytes in the pathophysiology of multiple sclerosis (MS) is discussed controversially. Especially the formation of the glial scar is often believed to act as a barrier for remyelination. At the same time, astrocytes are known to produce factors that influence oligodendrocyte precursor cell (OPC) survival. To explore these mechanisms, we investigated the astrocytic reaction in an animal model induced by immunization with myelin oligodendrocyte glycoprotein (MOG) in Dark Agouti (DA) rats, which mimics most of the histological features of MS. We correlated the astroglial reaction by immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP) to the remyelination capacity by in situ hybridization for mRNA of proteolipid protein (PLP), indicative of OPCs, over the full course of the disease. PLP mRNA peaked in early remyelinating lesions while the amount of GFAP positive astrocytes was highest in remyelinated lesions. In shadow plaques, we found at the same time all features of a glial scar and numbers of OPCs and mature oligodendrocytes, which were nearly equal to that in unaffected white matter areas. To assess the plaque environment, we furthermore quantitatively analyzed factors expressed by astrocytes previously suggested to influence remyelination. From our data, we conclude that remyelination occurs despite an abundant glial reaction in this animal model. The different patterns of astrocytic factors and the occurrence of different astrocytic phenotypes during lesion evolution furthermore indicate a finely regulated, balanced astrocytic involvement leading to successful repair.

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“…The improvement observed in PDGF for both overweight and normal weight participants represents another beneficial effect of exercise training; as it has been shown that a higher level of PDGF can reduce clinical consequences of damage in multiple sclerosis and increase progenitors and reversal of cell death in CNS (Huang and Dreyfus, 2016). Exercise research on PDGF is limited, Czarkowska-Paczek et al, found that endurance training enhanced PDGF expression in rat skeletal muscle (Czarkowska-Paczek et al, 2010); however, Trenerry et al, reported although acute exercise increased PDGF expression, there was no change after 12 weeks of resistance exercise (Trenerry et al, 2011).…”

Section: Exercise-related Neurotrophic Factors Modulationmentioning

confidence: 99%

“…Some of the evaluated markers in the current study are secreted from a variety of tissues. For example, BDNF is released from the brain, muscle, and some immune cells (Huang et al, 2014;Huang and Dreyfus, 2016;Onuoha et al, 1998).…”

Section: Limitation 14mentioning

confidence: 99%

Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis

et al. 2018

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Blood-brain barrier (BBB) and neurotrophic factors seemingly have an important role in multiple sclerosis pathology. Physical activity may influence blood-brain barrier function and levels of neurotrophic factors, and such effects might be moderated by body weight status. This study investigated the effect of exercise training on markers of blood-brain barrier permeability and neurotrophic factors as a function of weight status in multiple sclerosis patients. Sixty three persons with relapsing remitting multiple sclerosis who were normal weight (n: 33) or overweight (n: 33) were randomly assigned into groups of exercise (normal weight training, n: 18; overweight training group, n: 18) or no exercise (normal weight control, n: 15; overweight control group, n: 15). The intervention consisted of 8 weeks (3 days per week) of cycling undertaken at 60-70% peak power. Resting blood concentrations of s100 calcium-binding protein B (s100b) and neuron-specific enolase as BBB permeability markers, neurotrophic factors and cytokines (Interleukin-10 and tumor necrosis factor alpha) were evaluated before and after the intervention. There were significant weight, training, and interaction effects on brain-derived neurotrophic factor and platelet-derived growth factor; however, ciliary neurotrophic factor and nerve growth factor did not demonstrate any effect. Brain-derived neurotrophic factor and platelet-derived growth factor were significantly increased from pre-post in normal weight exercise. Significant weight, training, and interaction effects were found for s100b. In detail, s100b was significantly increased from pre-post in normal weight exercise. In contrast, neuron-specific enolase and cytokines did not demonstrate any effect. Generally, Exercise training may alter markers of BBB permeability and neurotrophic factor status in normal weight persons with multiple sclerosis; however, overweight participants may be more resistant to these effects of exercise.

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The role of growth factors as a therapeutic approach to demyelinating disease

Cited by 42 publications

References 198 publications

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

The formation of a glial scar does not prohibit remyelination in an animal model of multiple sclerosis

Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis

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