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Intranasal Delivery of Mitochondria Attenuates Brain Injury by AMPK and SIRT1/PGC-1α Pathways in a Murine Model of Photothrombotic Stroke

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Abstract

Ischemic stroke is one of the major causes of morbidity and mortality worldwide. Mitochondria play a vital role in the pathological processes of cerebral ischemic injury, but its transplantation and underlying mechanisms remain unclear. In the present study, we examined the effects of mitochondrial therapy on the modulation of AMPK and SIRT1/PGC-1α signaling pathway, oxidative stress, and NLRP3 inflammasome activation after photothrombotic ischemic stroke (pt-MCAO). The adult male mice were subjected to the pt-MCAO in which the proximal-middle cerebral artery was exposed with a 532-nm laser beam for 4 min by retro-orbital injection of a photosensitive dye (Rose Bengal: 15 mg/kg) before the laser light exposure and isolated mitochondria (100 μg protein) were administered intranasally at 30 min, 24 h, and 48 h following post-stroke. After 72 h, mice were tested for neurobehavioral outcomes and euthanized for infarct volume, brain edema, and molecular analysis. First, we found that mitochondria therapy significantly decreased brain infarct volume and brain edema, improved neurological dysfunction, attenuated ischemic stroke-induced oxidative stress, and neuroinflammation. Second, mitochondria treatment inhibited NLRP3 inflammasome activation. Finally, mitochondria therapy accelerated p-AMPKα(Thr172) and PGC-1α expression and resorted SIRT1 protein expression levels in pt-MCAO mice. In conclusion, our results demonstrate that mitochondria therapy exerts neuroprotective effects by inhibiting oxidative damage and inflammation, mainly dependent on the heightening activation of the AMPK and SIRT1/PGC-1α signaling pathway. Thus, intranasal delivery of mitochondria might be considered a new therapeutic strategy for ischemic stroke treatment.

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Data Availability

The data generated and analyzed in this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the UTHSC Bridge funding award (E073005058– Bridge Support-2022) and the National Institute of Health (R01-NS097800 and R56 NS127924-01) to T.I and DK117183 and DK132230 to A.B. The American Heart Association (AHA) Postdoctoral Fellowship 1029163 to M.S.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA

    Mohd. Salman, Arshi Parveen & Tauheed Ishrat

  2. Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-228, Memphis, TN, 38163, USA

    Mohd. Salman

  3. Transplant Research Institute, College of Medicine, The University of Tennessee Health Science Center, 71 S Manassas St, Room 418H, Memphis, TN, 38103, USA

    Amanda S Stayton & Amandeep Bajwa

  4. Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Kehkashan Parveen & Michelle A Puchowicz

  5. Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India

    Suhel Parvez

  6. Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA

    Amandeep Bajwa

  7. Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA

    Amandeep Bajwa

  8. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA

    Tauheed Ishrat

  9. Neuroscience Institute, The University of Tennessee Health Science Center, Memphis, TN, USA

    Tauheed Ishrat

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  1. Mohd. Salman
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  5. Michelle A Puchowicz
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  7. Amandeep Bajwa
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  8. Tauheed Ishrat
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Contributions

Mohd. Salman conducted all experiments, data analysis, writing of the first draft, and manuscript preparation. Amandeep Bajwa reviewed the manuscript. Amanda Stayton helped in mitochondria isolation and preparation and reviewed the manuscript. Kehkashan Parveen, Arshi Parveen, Michelle A Puchowicz, and Suhel Parvez helped with the experimental design and review of the manuscript. Tauheed Ishrat designed and oversaw the project, including experimental design, managed resources, and critically reviewed the manuscript.

Corresponding authors

Correspondence to Mohd. Salman, Amandeep Bajwa or Tauheed Ishrat.

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All procedures related to animal studies were approved by the institutional animal committee at UTHSC in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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Salman, M., Stayton, A.S., Parveen, K. et al. Intranasal Delivery of Mitochondria Attenuates Brain Injury by AMPK and SIRT1/PGC-1α Pathways in a Murine Model of Photothrombotic Stroke. Mol Neurobiol 61, 2822–2838 (2024). https://doi.org/10.1007/s12035-023-03739-4

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