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Intranasally administered IGF-1 inhibits spreading depression in vivo.

ABSTRACT: Spreading depression (SD) is a wave of cellular depolarization that travels slowly through susceptible gray matter brain areas. SD is the most likely cause of migraine aura and perhaps migraine pain, and is a well-accepted animal model of migraine. Identification of therapeutics that can prevent SD may have clinical relevance toward migraine treatment. Here we show that insulin-like growth factor-1 (IGF-1) significantly inhibited neocortical SD in vivo after intranasal delivery to rats. A single dose of IGF-1 inhibited SD within an hour, and continued to protect for at least seven days thereafter. A two-week course of IGF-1, administered every third day, further decreased SD susceptibility and showed no aberrant effects on glial activation, nasal mucosa, or serum markers of toxicity. SD begets SD in vitro by mechanisms that involve microglial activation. We add to this relationship by showing that recurrent SD in vivo increased susceptibility to subsequent SD, and that intervention with IGF-1 significantly interrupted this pathology. These findings support nasal administration of IGF-1 as a novel intervention capable of mitigating SD susceptibility, and as a result, potentially migraine.

SUBMITTER: Grinberg YY

PROVIDER: S-EPMC5993215 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Intranasally administered IGF-1 inhibits spreading depression in vivo.

Grinberg Yelena Y YY Zitzow Lois A LA Kraig Richard P RP

Brain research 20170923

Spreading depression (SD) is a wave of cellular depolarization that travels slowly through susceptible gray matter brain areas. SD is the most likely cause of migraine aura and perhaps migraine pain, and is a well-accepted animal model of migraine. Identification of therapeutics that can prevent SD may have clinical relevance toward migraine treatment. Here we show that insulin-like growth factor-1 (IGF-1) significantly inhibited neocortical SD in vivo after intranasal delivery to rats. A single ...[more]

PMID: 28951235

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Project description:Background Middle East respiratory syndrome coronavirus (MERS-CoV), a new coronavirus that emerged in 2012, causes severe and fatal acute respiratory illness in man. Its high mortality (roughly 38%) has raised public fear worldwide, calling for the development of effective and safe therapeutics to combat MERS-CoV infection. On the basis of our previous work in development of peptide fusion inhibitors against HIV and SARS-CoV, and the crystal structure of the six-helix-bundle core of the MERS-CoV spike protein, we identified a peptide derived from the MERS-CoV S protein S2 subunit HR2 domain (HR2P) with a potent inhibitory activity against S-protein-mediated cell–cell fusion. Here, we tested an HR2P analogue with improved pharmaceutical properties, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo (appendix). Methods We assessed the anti-MERS-CoV activities of HR2P-M2 in vitro with pseudotyped MERS-CoVs in cell culture and in vivo with live MERS-CoVs in hDPP4-transgenic mice. The activities of HR2P-M2 to form six-helix bundles with HR1 peptides and to block fusion core formation between HR1 and HR2 peptides were studied using methods such as circular dichroism, N-PAGE, and FN-PAGE. Findings HR2P-M2 was highly effective in blockade of cell–cell fusion mediated by MERS-CoV S proteins and inhibition of infection by MERS pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region, with IC50 (the concentration causing 50% inhibition) less than 0·7 ?M. HR2P-M2 bound to the HR1 peptide to form stable six-helix bundles and blocked fusion core formation between the HR1 and HR2 peptides. Intranasal administration of HR2P-M2 before viral challenge fully protected hDPP4-transgenic mice (n=5) from MERS-CoV infection, whereas all the untreated mice (n=5) died 8 days after viral challenge. Interpretation Our findings suggest that the HR2P-M2 peptide merits further development as an effective and safe anti-MERS-CoV drug, alone or in combination with other antiviral drugs, to treat MERS-CoV-infected patients and to prevent the disease in high-risk populations, including health-care workers and family members of patients. Funding This work was supported by grants from the National Science Fund of China (81173098 and 81361120378 to SJ, 81373456 to LL), the National 973 Program of China (2012CB519001 to SJ), and the US National Biocontainment Laboratories Operations Support (5UC7AI094660-05 to C-TKT). The funders had no role in interpretation of the findings and writing of this abstract.

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Intranasally administered IGF-1 inhibits spreading depression in vivo.

Publications

Intranasally administered IGF-1 inhibits spreading depression in vivo.

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