G-1 Exerts Neuroprotective Effects Through G Protein



BIOSCIENCE REPORTS

ACCEPTED MANUSCRIPT

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Cite as Bioscience Reports (2016) DOI: 10.1042/BSR20160134

Copyright 2016 The Author(s). This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence. All other rights reserved.

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7KHDXWKRUKDVQRFRQIOLFWVRILQWHUHVWWRGHFODUH   5()(5(1&(6 ϭ͘ ĂŝD͕DĂz>͕YŝŶWĞƚĂů͘;ϮϬϭϰͿdŚĞůŽƐƐŽĨĞƐƚƌŽŐĞŶĞĨĨŝĐĂĐLJĂŐĂŝŶƐƚĐĞƌĞďƌĂůŝƐĐŚĞŵŝĂŝŶĂŐĞĚƉŽƐƚŵĞŶŽƉĂƵƐĂůĨĞŵĂůĞ ŵŝĐĞ͘EĞƵƌŽƐĐŝ>Ğƚƚ͘ϱϱϴ͗ϭϭϱͲϭϭϵ͘ Ϯ͘ ^ĐŽƚƚ͕ŚĂŶŐY'͕tĂŶŐZ͕sĂĚůĂŵƵĚŝZ͕ƌĂŶŶ͘;ϮϬϭϮͿƐƚƌŽŐĞŶŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶĂŶĚƚŚĞĐƌŝƚŝĐĂůƉĞƌŝŽĚŚLJƉŽƚŚĞƐŝƐ͘ &ƌŽŶƚEĞƵƌŽĞŶĚŽĐƌŝŶŽů͘ϯϯ͗ϴϱͲϭϬϰ͘ ϯ͘ ^ĐŚĂƵǁĞĐŬĞƌW͕tŽŽĚZ/͕>ŽƌĞŶnjĂŶĂ͘;ϮϬϬϵͿEĞƵƌŽƉƌŽƚĞĐƚŝŽŶĂŐĂŝŶƐƚĞdžĐŝƚŽƚŽdžŝĐďƌĂŝŶŝŶũƵƌLJŝŶŵŝĐĞĂĨƚĞƌŽǀĂƌŝĂŶ ƐƚĞƌŽŝĚĚĞƉůĞƚŝŽŶ͘ƌĂŝŶZĞƐ͘ϭϮϲϱ͗ϯϳͲϰϲ͘ ϰ͘ ĞƉLJƉĞƌĞ,͕/ŶŬŝW͘;ϮϬϭϱͿdŚĞůĞǀŽŶŽƌŐĞƐƚƌĞůͲƌĞůĞĂƐŝŶŐŝŶƚƌĂƵƚĞƌŝŶĞƐLJƐƚĞŵĨŽƌĞŶĚŽŵĞƚƌŝĂůƉƌŽƚĞĐƚŝŽŶĚƵƌŝŶŐĞƐƚƌŽŐĞŶ ƌĞƉůĂĐĞŵĞŶƚƚŚĞƌĂƉLJ͗ĂĐůŝŶŝĐĂůƌĞǀŝĞǁ͘ůŝŵĂĐƚĞƌŝĐ͘ϭϴ͗ϰϳϬͲϰϴϮ͘ ϱ͘ tĂƐƐĞƌƚŚĞŝůͲ^ŵŽůůĞƌ^͕,ĞŶĚƌŝdž^>͕>ŝŵĂĐŚĞƌDĞƚĂů͘;ϮϬϬϯͿĨĨĞĐƚŽĨĞƐƚƌŽŐĞŶƉůƵƐƉƌŽŐĞƐƚŝŶŽŶƐƚƌŽŬĞŝŶ ƉŽƐƚŵĞŶŽƉĂƵƐĂůǁŽŵĞŶ͗ƚŚĞtŽŵĞŶΖƐ,ĞĂůƚŚ/ŶŝƚŝĂƚŝǀĞ͗ĂƌĂŶĚŽŵŝnjĞĚƚƌŝĂů͘:D͘Ϯϴϵ͗ϮϲϳϯͲϮϲϴϰ͘ ϲ͘ DĂz͕'ƵŽ,͕ŚĂŶŐ>ĞƚĂů͘;ϮϬϭϲͿƐƚƌŽŐĞŶƌĞƉůĂĐĞŵĞŶƚƚŚĞƌĂƉLJͲŝŶĚƵĐĞĚŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶĂŐĂŝŶƐƚďƌĂŝŶ ŝƐĐŚĞŵŝĂͲƌĞƉĞƌĨƵƐŝŽŶŝŶũƵƌLJŝŶǀŽůǀĞƐƚŚĞĂĐƚŝǀĂƚŝŽŶŽĨĂƐƚƌŽĐLJƚĞƐǀŝĂĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌďĞƚĂ͘^ĐŝZĞƉ͘ϲ͗Ϯϭϰϲϳ͘ ϳ͘ WĂƚĞƌŶŝ/͕ĞƌƚŝŶŝ^͕'ƌĂŶĐŚŝ͕DĂĐĐŚŝĂD͕DŝŶƵƚŽůŽ&͘;ϮϬϭϯͿƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌůŝŐĂŶĚƐ͗ĂƉĂƚĞŶƚƌĞǀŝĞǁƵƉĚĂƚĞ͘džƉĞƌƚ KƉŝŶdŚĞƌWĂƚ͘Ϯϯ͗ϭϮϰϳͲϭϮϳϭ͘ ϴ͘ ŚĂŶĚĂƉĂŶŝŝy͕ŚĂŽD'͘;ϮϬϭϭͿEĞƵƌŽƉƌŽƚĞĐƚŝǀĞĞĨĨĞĐƚƐŽĨŽĞƐƚƌŽŐĞŶĂŐĂŝŶƐƚŽdžŝĚĂƚŝǀĞƚŽdžŝĐŝƚLJ ƚŚƌŽƵŐŚĂĐƚŝǀĂƚŝŽŶŽĨ'ͲƉƌŽƚĞŝŶͲĐŽƵƉůĞĚƌĞĐĞƉƚŽƌϯϬƌĞĐĞƉƚŽƌ͘ůŝŶdžƉWŚĂƌŵĂĐŽůWŚLJƐŝŽů͘ϯϴ͗ϱϳϳͲϱϴϱ͘ ϭϯ͘ ŝ>͕yŝŽŶŐz͕YŝĂŶDĞƚĂů͘;ϮϬϭϰͿŽŵƉůĞŵĞŶƚϱĂŝƐĚĞƚƌŝŵĞŶƚĂůƚŽŚŝƐƚŽůŽŐŝĐĂůĂŶĚĨƵŶĐƚŝŽŶĂůůŽĐŽŵŽƚŽƌƌĞĐŽǀĞƌLJ ĂĨƚĞƌƐƉŝŶĂůĐŽƌĚŝŶũƵƌLJŝŶŵŝĐĞ͘EĞƵƌŽďŝŽůŽŐLJŽĨŝƐĞĂƐĞ͘ϲϲ͗ϳϰͲϴϮ͘

Ϯϰ͘

ĂƐƐŽD͕&ŝƐŚĞƌ>͕ŶĚĞƌƐŽŶ:͕:ĂŬĞŵĂŶ>͕DĐdŝŐƵĞD͕WŽƉŽǀŝĐŚW'͘;ϮϬϬϲͿĂƐƐŽDŽƵƐĞ^ĐĂůĞĨŽƌůŽĐŽŵŽƚŝŽŶ ĚĞƚĞĐƚƐĚŝĨĨĞƌĞŶĐĞƐŝŶƌĞĐŽǀĞƌLJĂĨƚĞƌƐƉŝŶĂůĐŽƌĚŝŶũƵƌLJŝŶĨŝǀĞĐŽŵŵŽŶŵŽƵƐĞƐƚƌĂŝŶƐ͘:EĞƵƌŽƚƌĂƵŵĂ͘Ϯϯ͗ϲϯϱͲϲϱϵ͘

Ϯϱ͘

ZŝǀůŝŶ^͕dĂƚŽƌ,͘;ϭϵϳϳͿKďũĞĐƚŝǀĞĐůŝŶŝĐĂůĂƐƐĞƐƐŵĞŶƚŽĨŵŽƚŽƌĨƵŶĐƚŝŽŶĂĨƚĞƌĞdžƉĞƌŝŵĞŶƚĂůƐƉŝŶĂůĐŽƌĚŝŶũƵƌLJŝŶƚŚĞ ƌĂƚ͘:EĞƵƌŽƐƵƌŐ͘ϰϳ͗ϱϳϳͲϱϴϭ͘

Ϯϲ͘

ĚĞĂƐƐŝĂ^ĂŵƉĂŝŽK͕ĞĨŝŶŽ,>͕ĞůĞůĞůůƵnj'ƵŝŵĂƌĂĞƐ͘;ϮϬϭϲͿĨĨĞĐƚŽĨŚLJƉŽǀŽůĞŵŝĂŽŶƚƌĂƵŵĂƚŝĐƐƉŝŶĂůĐŽƌĚ ŝŶũƵƌLJ͘^ƉŝŶĂůŽƌĚ͘

Ϯϳ͘

,ƵĂŶŐ^Y͕dĂŶŐ>͕^ƵŶ^YĞƚĂů͘;ϮϬϭϰͿĞŵLJĞůŝŶĂƚŝŽŶ/ŶŝƚŝĂƚĞĚďLJKůŝŐŽĚĞŶĚƌŽĐLJƚĞƉŽƉƚŽƐŝƐƚŚƌŽƵŐŚŶŚĂŶĐŝŶŐ ŶĚŽƉůĂƐŵŝĐZĞƚŝĐƵůƵŵͲDŝƚŽĐŚŽŶĚƌŝĂ/ŶƚĞƌĂĐƚŝŽŶƐĂŶĚ/ĚϮdžƉƌĞƐƐŝŽŶĂĨƚĞƌŽŵƉƌĞƐƐĞĚ^ƉŝŶĂůŽƌĚ/ŶũƵƌLJŝŶZĂƚƐ͘ŶƐ EĞƵƌŽƐĐŝĞŶĐĞΘdŚĞƌĂƉĞƵƚŝĐƐ͘ϮϬ͗ϮϬͲϯϭ͘

Ϯϴ͘

&ĂƌŽŽƋƵĞD͘;ϮϬϬϬͿ^ƉŝŶĂůĐŽƌĚĐŽŵƉƌĞƐƐŝŽŶŝŶũƵƌLJŝŶƚŚĞŵŽƵƐĞ͗ƉƌĞƐĞŶƚĂƚŝŽŶŽĨĂŵŽĚĞůŝŶĐůƵĚŝŶŐĂƐƐĞƐƐŵĞŶƚŽĨ ŵŽƚŽƌĚLJƐĨƵŶĐƚŝŽŶ͘ĐƚĂEĞƵƌŽƉĂƚŚŽů͘ϭϬϬ͗ϭϯͲϮϮ͘

Ϯϵ͘

^ŽŚƌĂďũŝ&͘;ϮϬϭϱͿƐƚƌŽŐĞŶͲ/'&ͲϭŝŶƚĞƌĂĐƚŝŽŶƐŝŶŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶ͗ŝƐĐŚĞŵŝĐƐƚƌŽŬĞĂƐĂĐĂƐĞƐƚƵĚLJ͘&ƌŽŶƚ EĞƵƌŽĞŶĚŽĐƌŝŶŽů͘ϯϲ͗ϭͲϭϰ͘

ϯϬ͘

&ŝŽĐĐŚĞƚƚŝD͕ƐĐĞŶnjŝW͕DĂƌŝŶŽD͘;ϮϬϭϮͿEĞƵƌŽƉƌŽƚĞĐƚŝǀĞĞĨĨĞĐƚƐŽĨϭϳďĞƚĂͲĞƐƚƌĂĚŝŽůƌĞůLJŽŶĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌ ŵĞŵďƌĂŶĞŝŶŝƚŝĂƚĞĚƐŝŐŶĂůƐ͘&ƌŽŶƚWŚLJƐŝŽů͘ϯ͗ϳϯ͘

ϯϭ͘

^ŚƵŐŚƌƵĞW:͕>ĂŶĞDs͕DĞƌĐŚĞŶƚŚĂůĞƌ/͘;ϭϵϵϳͿŽŵƉĂƌĂƚŝǀĞĚŝƐƚƌŝďƵƚŝŽŶŽĨĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌͲĂůƉŚĂĂŶĚͲďĞƚĂŵZEŝŶ

ϯϮ͘

DĞƌĐŚĞŶƚŚĂůĞƌ/͕>ĂŶĞDs͕EƵŵĂŶ^͕ĞůůŽǀĂĚĞd>͘;ϮϬϬϰͿŝƐƚƌŝďƵƚŝŽŶŽĨĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌĂůƉŚĂĂŶĚďĞƚĂŝŶƚŚĞ

ƚŚĞƌĂƚĐĞŶƚƌĂůŶĞƌǀŽƵƐƐLJƐƚĞŵ͘:ŽŵƉEĞƵƌŽů͘ϯϴϴ͗ϱϬϳͲϱϮϱ͘ ŵŽƵƐĞĐĞŶƚƌĂůŶĞƌǀŽƵƐƐLJƐƚĞŵ͗ŝŶǀŝǀŽĂƵƚŽƌĂĚŝŽŐƌĂƉŚŝĐĂŶĚŝŵŵƵŶŽĐLJƚŽĐŚĞŵŝĐĂůĂŶĂůLJƐĞƐ͘:ŽŵƉEĞƵƌŽů͘ ϰϳϯ͗ϮϳϬͲϮϵϭ͘ ϯϯ͘

WůĂƚĂŶŝĂW͕^ĞŵŝŶĂƌĂ'͕ƌŽŶŝĐĂ͕dƌŽŽƐƚ͕sŝŶĐĞŶnjĂĂƚĂŶŝĂD͕ŶŐĞůĂ^ŽƌƚŝŶŽD͘;ϮϬϬϱͿϭϳďĞƚĂͲĞƐƚƌĂĚŝŽůƌĞƐĐƵĞƐ

ϯϰ͘

DŽƌŝƐƐĞƚƚĞD͕:ŽƵƌĚĂŝŶ^͕ů^ǁĞŝĚŝ^͕DĞŶŶŝƚŝ&^͕ZĂŵŝƌĞnj͕ŝWĂŽůŽd͘;ϮϬϬϳͿZŽůĞŽĨĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌƐŝŶ

ƐƉŝŶĂůŵŽƚŽŶĞƵƌŽŶƐĨƌŽŵDWͲŝŶĚƵĐĞĚƚŽdžŝĐŝƚLJ͗ĂƌŽůĞĨŽƌŐůŝĂůĐĞůůƐ͘EĞƵƌŽďŝŽůŝƐ͘ϮϬ͗ϰϲϭͲϰϳϬ͘ ŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶďLJĞƐƚƌĂĚŝŽůĂŐĂŝŶƐƚDWdWƚŽdžŝĐŝƚLJ͘EĞƵƌŽƉŚĂƌŵĂĐŽůŽŐLJ͘ϱϮ͗ϭϱϬϵͲϭϱϮϬ͘ ϯϱ͘

tĂŶŐY͕^ĂŶƚŝnjŽZ͕ĂƵŐŚŵĂŶs>͕WĞůůŝŐƌŝŶŽ͕/ĂĚĞĐŽůĂ͘;ϭϵϵϵͿƐƚƌŽŐĞŶƉƌŽǀŝĚĞƐŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶŝŶƚƌĂŶƐŝĞŶƚ

ϯϲ͘

^ƉĞŶĐĞZ͕tŝƐĚŽŵ:͕ĂŽzĞƚĂů͘;ϮϬϭϯͿƐƚƌŽŐĞŶŵĞĚŝĂƚĞƐŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶĂŶĚĂŶƚŝͲŝŶĨůĂŵŵĂƚŽƌLJĞĨĨĞĐƚƐĚƵƌŝŶŐ

ĨŽƌĞďƌĂŝŶŝƐĐŚĞŵŝĂƚŚƌŽƵŐŚƉĞƌĨƵƐŝŽŶͲŝŶĚĞƉĞŶĚĞŶƚŵĞĐŚĂŶŝƐŵƐŝŶƌĂƚƐ͘^ƚƌŽŬĞ͘ϯϬ͗ϲϯϬͲϲϯϳ͘ ƚŚƌŽƵŐŚZĂůƉŚĂƐŝŐŶĂůŝŶŐŽŶĂƐƚƌŽĐLJƚĞƐďƵƚŶŽƚƚŚƌŽƵŐŚZďĞƚĂƐŝŐŶĂůŝŶŐŽŶĂƐƚƌŽĐLJƚĞƐŽƌŶĞƵƌŽŶƐ͘:EĞƵƌŽƐĐŝ͘ ϯϯ͗ϭϬϵϮϰͲϭϬϵϯϯ͘

ϯϳ͘

ŚĂŽ>͕tƵdt͕ƌŝŶƚŽŶZ͘;ϮϬϬϰͿƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌƐƵďƚLJƉĞƐĂůƉŚĂĂŶĚďĞƚĂĐŽŶƚƌŝďƵƚĞƚŽŶĞƵƌŽƉƌŽƚĞĐƚŝŽŶĂŶĚ

ϯϴ͘

ŝƵE:͕ŚĂŬƌĂďĂƌƚŝ^͕^ĐŚŶĞůů^͕tĞƐƐĞŶĚŽƌĨD͕'ŝŶƚnjůĞƌZ͘;ϮϬϭϭͿ^ƉŝŶĂůƐLJŶƚŚĞƐŝƐŽĨĞƐƚƌŽŐĞŶĂŶĚĐŽŶĐŽŵŝƚĂŶƚ ƐŝŐŶĂůŝŶŐďLJŵĞŵďƌĂŶĞĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌƐƌĞŐƵůĂƚĞƐƉŝŶĂůŬĂƉƉĂͲĂŶĚŵƵͲŽƉŝŽŝĚƌĞĐĞƉƚŽƌŚĞƚĞƌŽĚŝŵĞƌŝnjĂƚŝŽŶĂŶĚ ĨĞŵĂůĞͲƐƉĞĐŝĨŝĐƐƉŝŶĂůŵŽƌƉŚŝŶĞĂŶƚŝŶŽĐŝĐĞƉƚŝŽŶ͘:EĞƵƌŽƐĐŝ͘ϯϭ͗ϭϭϴϯϲͲϭϭϴϰϱ͘

ϰϭ͘

ŽƵƌƋƵĞD͕DŽƌŝƐƐĞƚƚĞD͕ŝWĂŽůŽd͘;ϮϬϭϱͿEĞƵƌŽƉƌŽƚĞĐƚŝŽŶŝŶWĂƌŬŝŶƐŽŶŝĂŶͲƚƌĞĂƚĞĚŵŝĐĞǀŝĂĞƐƚƌŽŐĞŶƌĞĐĞƉƚŽƌĂůƉŚĂ

ϰϮ͘

ŚƵ͕tĂŶŐ^͕tĂŶŐĞƚĂů͘;ϮϬϭϱͿϭϳďĞƚĂͲƐƚƌĂĚŝŽůƵƉͲƌĞŐƵůĂƚĞƐEƌĨϮǀŝĂW/ϯ