Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury
Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) i...
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| Format: | Article |
| Language: | English |
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Mary Ann Liebert
2024-11-01
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| Series: | Neurotrauma Reports |
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| Online Access: | https://www.liebertpub.com/doi/10.1089/neur.2024.0060 |
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| _version_ | 1849321777802510336 |
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| author | Lulin Li Andy Nguyen Brian Zhao Ryan Vest Lakshmi Yerra Bryan Sun Jian Luo |
| author_facet | Lulin Li Andy Nguyen Brian Zhao Ryan Vest Lakshmi Yerra Bryan Sun Jian Luo |
| author_sort | Lulin Li |
| collection | DOAJ |
| description | Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development. Aberrant TGF-β signaling is implicated in vascular pathologies associated with various neurological conditions. We recently developed a novel small molecule drug, C381, a TGF-β activator with the ability to restore lysosomal function. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether C381 would attenuate vascular injury. We first employed RNA-seq analysis to investigate the gene expression patterns associated with mTBI and evaluated the therapeutic potential of C381 in mitigating these changes. Our results demonstrate distinct mTBI-related gene expression signatures, prominently implicating pathways related to vascular integrity and endothelial function. Notably, treatment with C381 reversed these mTBI-induced gene expression changes. Immunohistochemical analysis further corroborated these findings, revealing that C381 treatment attenuated vascular damage in mTBI-affected brain tissue. These findings strongly support the potential clinical usefulness of C381 as a novel therapeutic intervention for mTBI. |
| format | Article |
| id | doaj-art-ad75c84b147c49e5b085f44e4d16628b |
| institution | Kabale University |
| issn | 2689-288X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Mary Ann Liebert |
| record_format | Article |
| series | Neurotrauma Reports |
| spelling | doaj-art-ad75c84b147c49e5b085f44e4d16628b2025-08-20T03:49:37ZengMary Ann LiebertNeurotrauma Reports2689-288X2024-11-01511016102610.1089/neur.2024.0060Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic InjuryLulin Li0Andy Nguyen1Brian Zhao2Ryan Vest3Lakshmi Yerra4Bryan Sun5Jian Luo6Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Department of Chemical Engineering, Stanford University, Stanford, California, USA.Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development. Aberrant TGF-β signaling is implicated in vascular pathologies associated with various neurological conditions. We recently developed a novel small molecule drug, C381, a TGF-β activator with the ability to restore lysosomal function. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether C381 would attenuate vascular injury. We first employed RNA-seq analysis to investigate the gene expression patterns associated with mTBI and evaluated the therapeutic potential of C381 in mitigating these changes. Our results demonstrate distinct mTBI-related gene expression signatures, prominently implicating pathways related to vascular integrity and endothelial function. Notably, treatment with C381 reversed these mTBI-induced gene expression changes. Immunohistochemical analysis further corroborated these findings, revealing that C381 treatment attenuated vascular damage in mTBI-affected brain tissue. These findings strongly support the potential clinical usefulness of C381 as a novel therapeutic intervention for mTBI.https://www.liebertpub.com/doi/10.1089/neur.2024.0060mild traumatic brain injurysmall moleculetherapyvascular injury |
| spellingShingle | Lulin Li Andy Nguyen Brian Zhao Ryan Vest Lakshmi Yerra Bryan Sun Jian Luo Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury Neurotrauma Reports mild traumatic brain injury small molecule therapy vascular injury |
| title | Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury |
| title_full | Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury |
| title_fullStr | Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury |
| title_full_unstemmed | Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury |
| title_short | Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury |
| title_sort | small molecule drug c381 attenuates brain vascular damage following repetitive mild traumatic injury |
| topic | mild traumatic brain injury small molecule therapy vascular injury |
| url | https://www.liebertpub.com/doi/10.1089/neur.2024.0060 |
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