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Genetic and Pharmacological Modulation of P75 Neurotrophin Receptor Attenuate Brain Damage After Ischemic Stroke in Mice

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Abstract

The precursor nerve growth factor (ProNGF) and its receptor p75 neurotrophin receptor (p75NTR) are upregulated in several brain diseases, including ischemic stroke. The activation of p75NTR is associated with neuronal apoptosis and inflammation. Thus, we hypothesized that p75NTR modulation attenuates brain damage and improves functional outcomes after ischemic stroke. Two sets of experiments were performed. (1) Adult wild-type (WT) C57BL/6 J mice were subjected to intraluminal suture-middle cerebral artery occlusion (MCAO) to induce cerebral ischemia. Pharmacological inhibitor of p75NTR, LM11A-31 (50 mg/kg), or normal saline was administered intraperitoneally (IP) 1 h post-MCAO, and animals survived for 24 h. (2) Adult p75NTR heterozygous knockout (p75NTR+/−) and WT were subjected to photothrombotic (pMCAO) to induce ischemic stroke, and the animals survived for 72 h. The sensory-motor function of animals was measured using Catwalk XT. The brain samples were collected to assess infarction volume, edema, hemorrhagic transformation, neuroinflammation, and signaling pathway at 24 and 72 h after the stroke. The findings described that pharmacological inhibition and genetic knocking down of p75NTR reduce infarction size, edema, and hemorrhagic transformation following ischemic stroke. Additionally, p75NTR modulation significantly decreased several anti-apoptosis markers and improved sensory motor function compared to the WT mice following ischemic stroke. Our observations exhibit that the involvement of p75NTR in ischemic stroke and modulation of p75NTR could improve the outcome of ischemic stroke by increasing cell survival and enhancing motor performance. LM11A-31 has the potential to be a promising therapeutic agent for ischemic stroke. However, more evidence is needed to illuminate the efficacy of LM11A-31 in ischemic stroke.

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Data Availability

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

Code Availability

Not applicable

Abbreviations

AD:

Alzheimer’s disease

Akt:

Protein kinase B

Bax:

Bcl-2 associated X protein

BBB:

Blood-brain barrier

Bcl-2:

B-cell lymphoma 2

BDNF:

Brain-derived neurotrophic factor

CNSL:

Central nervous system

dMCAO:

Distal-middle cerebral artery occlusion

CBF:

Cerebral blood flow

ERK½:

Extracellular signal-regulated kinase

GSK3β:

Glycogen synthase kinase 3 beta

HT:

Hemorrhagic transformation

IP:

Intraperitoneally

JNK:

C-Jun N-terminal kinase

MCAO:

Middle cerebral artery occlusion

NFκB:

Nuclear factor kappa- light- chain- enhancer of activated B cells

NGF:

Nerve growth factor

NT-3:

Neurotrophin-3

NT-4:

Neurotrophin-4

P75NTR+/− :

P75NTR heterozygous knock out

ProNGF:

Precursor nerve growth factor

pMCAO:

Photothrombotic middle cerebral artery occlusion

RhoA:

Ras homolog gene family member A

TBI:

Traumatic brain injury

TNF-α:

Tumor necrosis factor-alpha

Trk:

Tyrosine receptor kinase

tPA:

Tissue plasminogen activator

WT:

Wild type

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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 TI.

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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

    Golnoush Mirzahosseini, Mohd Salman & Tauheed Ishrat

  2. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, TN, 38163, Memphis, USA

    Golnoush Mirzahosseini, Santosh Kumar & Tauheed Ishrat

  3. Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, LA, 70112, New Orleans, USA

    Saifudeen Ismael

  4. Neuroscience Institute, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Tauheed Ishrat

Authors
  1. Golnoush Mirzahosseini
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  2. Saifudeen Ismael
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  3. Mohd Salman
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  4. Santosh Kumar
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Contributions

Golnoush Mirzahosseini—conducted experiments, result analysis, writing of the first draft . Saifudeen Ismael conducted experiments and helped data analysis and Mohd. Salman—reviewed the manuscript and data analysis. Santosh Kumar—critically reviewed the manuscript. Tauheed Ishrat—designed and oversaw the whole project including experimental design, managing resources and critically reviewed the manuscript.

Corresponding author

Correspondence to 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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Mirzahosseini, G., Ismael, S., Salman, M. et al. Genetic and Pharmacological Modulation of P75 Neurotrophin Receptor Attenuate Brain Damage After Ischemic Stroke in Mice. Mol Neurobiol 61, 276–293 (2024). https://doi.org/10.1007/s12035-023-03550-1

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  • DOI: https://doi.org/10.1007/s12035-023-03550-1

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