Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats
(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups w...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/22/2659 |
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| author | Madeleine J. Smith Tayla Penny Yen Pham Amy E. Sutherland Graham Jenkin Michael C. Fahey Madison C. B. Paton Megan Finch-Edmondson Suzanne L. Miller Courtney A. McDonald |
| author_facet | Madeleine J. Smith Tayla Penny Yen Pham Amy E. Sutherland Graham Jenkin Michael C. Fahey Madison C. B. Paton Megan Finch-Edmondson Suzanne L. Miller Courtney A. McDonald |
| author_sort | Madeleine J. Smith |
| collection | DOAJ |
| description | (1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic–ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (<i>p</i> < 0.05 compared to control). In contrast, only the highest dose of tacrolimus administered post-HI (0.25 mg/kg/day) reduced brain infarct size (<i>p</i> < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation. |
| first_indexed | 2024-03-09T16:55:33Z |
| format | Article |
| id | doaj.art-3d4c13f9aded4afa9e7aaa537e5ae941 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T16:55:33Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3d4c13f9aded4afa9e7aaa537e5ae9412023-11-24T14:35:31ZengMDPI AGCells2073-44092023-11-011222265910.3390/cells12222659Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in RatsMadeleine J. Smith0Tayla Penny1Yen Pham2Amy E. Sutherland3Graham Jenkin4Michael C. Fahey5Madison C. B. Paton6Megan Finch-Edmondson7Suzanne L. Miller8Courtney A. McDonald9The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaCerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, AustraliaCerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic–ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (<i>p</i> < 0.05 compared to control). In contrast, only the highest dose of tacrolimus administered post-HI (0.25 mg/kg/day) reduced brain infarct size (<i>p</i> < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation.https://www.mdpi.com/2073-4409/12/22/2659immune systemimmunosuppressionneonatal brain injuryneuroprotectionT-cells |
| spellingShingle | Madeleine J. Smith Tayla Penny Yen Pham Amy E. Sutherland Graham Jenkin Michael C. Fahey Madison C. B. Paton Megan Finch-Edmondson Suzanne L. Miller Courtney A. McDonald Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats Cells immune system immunosuppression neonatal brain injury neuroprotection T-cells |
| title | Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats |
| title_full | Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats |
| title_fullStr | Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats |
| title_full_unstemmed | Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats |
| title_short | Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats |
| title_sort | neuroprotective action of tacrolimus before and after onset of neonatal hypoxic ischaemic brain injury in rats |
| topic | immune system immunosuppression neonatal brain injury neuroprotection T-cells |
| url | https://www.mdpi.com/2073-4409/12/22/2659 |
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