LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice

Shuhei Ito, Narihito Nagoshi, Osahiko Tsuji, Shinsuke Shibata, Munehisa Shinozaki, Soya Kawabata, Kota Kojima, Kaori Yasutake, Tomoko Hirokawa, Morio Matsumoto, Kohtaro Takei, Masaya Nakamura, Hideyuki Okano

Research output: Contribution to journalArticle

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Abstract

Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.

Original languageEnglish
JournaleNeuro
Volume5
Issue number5
DOIs
Publication statusPublished - 2018 Sep 1

Fingerprint

Olfactory Bulb
Spinal Cord Injuries
Regeneration
Apoptosis
Pyramidal Tracts
Neuroprotective Agents
Transgenic Mice
Motor Evoked Potentials
Growth Cones
Recovery of Function
Therapeutic Uses
Spinal Cord
Wounds and Injuries

Keywords

  • axonal regeneration
  • LOTUS
  • neuronal protection
  • Nogo receptor
  • spinal cord injury
  • transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice. / Ito, Shuhei; Nagoshi, Narihito; Tsuji, Osahiko; Shibata, Shinsuke; Shinozaki, Munehisa; Kawabata, Soya; Kojima, Kota; Yasutake, Kaori; Hirokawa, Tomoko; Matsumoto, Morio; Takei, Kohtaro; Nakamura, Masaya; Okano, Hideyuki.

In: eNeuro, Vol. 5, No. 5, 01.09.2018.

Research output: Contribution to journalArticle

Ito, Shuhei ; Nagoshi, Narihito ; Tsuji, Osahiko ; Shibata, Shinsuke ; Shinozaki, Munehisa ; Kawabata, Soya ; Kojima, Kota ; Yasutake, Kaori ; Hirokawa, Tomoko ; Matsumoto, Morio ; Takei, Kohtaro ; Nakamura, Masaya ; Okano, Hideyuki. / LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice. In: eNeuro. 2018 ; Vol. 5, No. 5.
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AU - Shinozaki, Munehisa

AU - Kawabata, Soya

AU - Kojima, Kota

AU - Yasutake, Kaori

AU - Hirokawa, Tomoko

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N2 - Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.

AB - Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.

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