Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats
Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/14/24/5286 |
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| author | Aarón Del Pozo Laura Silva Angela Romero María De Hoz-Rivera María Villa María Martínez-Vega María Eugenia Prados Eduardo Muñoz José Martínez-Orgado |
| author_facet | Aarón Del Pozo Laura Silva Angela Romero María De Hoz-Rivera María Villa María Martínez-Vega María Eugenia Prados Eduardo Muñoz José Martínez-Orgado |
| author_sort | Aarón Del Pozo |
| collection | DOAJ |
| description | Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress. |
| first_indexed | 2024-03-09T16:00:01Z |
| format | Article |
| id | doaj.art-21a0875646f14f7daf7368d3221fd52f |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-09T16:00:01Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-21a0875646f14f7daf7368d3221fd52f2023-11-24T17:08:41ZengMDPI AGNutrients2072-66432022-12-011424528610.3390/nu14245286Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature RatsAarón Del Pozo0Laura Silva1Angela Romero2María De Hoz-Rivera3María Villa4María Martínez-Vega5María Eugenia Prados6Eduardo Muñoz7José Martínez-Orgado8Biomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainVivacell Biotechnology España S.L.U., 14014 Córdoba, SpainMaimonides Biomedical Research Institute of Córdoba, University of Córdoba, 14004 Córdoba, SpainBiomedical Research Foundation, Hospital Clínico San Carlos—IdISSC, 28040 Madrid, SpainIntraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.https://www.mdpi.com/2072-6643/14/24/5286betulinic acid hydroxamateintraventricular hemorrhageneuroprotectionprematurityrats |
| spellingShingle | Aarón Del Pozo Laura Silva Angela Romero María De Hoz-Rivera María Villa María Martínez-Vega María Eugenia Prados Eduardo Muñoz José Martínez-Orgado Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats Nutrients betulinic acid hydroxamate intraventricular hemorrhage neuroprotection prematurity rats |
| title | Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats |
| title_full | Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats |
| title_fullStr | Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats |
| title_full_unstemmed | Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats |
| title_short | Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats |
| title_sort | neuroprotective effects of betulinic acid hydroxamate in intraventricular hemorrhage induced brain damage in immature rats |
| topic | betulinic acid hydroxamate intraventricular hemorrhage neuroprotection prematurity rats |
| url | https://www.mdpi.com/2072-6643/14/24/5286 |
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