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INNOSC Theranostics and
Pharmacological Sciences Novel pharmacologic therapies for SAH

inflammation, and mitigates apoptosis in SAH rats by Moreover, the potential involvement of PRDX6 in the
suppressing iNOS expression, enhancing tight junction neuroprotective effects of Fer-1, a selective ferroptosis
proteins, and inhibiting the SIRT6/PCSK9 pathway . In inhibitor, in SAH has not been explored. The study
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SAH rats, the protective effects of dendritic cell exosomes employed endovascular perforation to induce a SAH
are further reinforced, with miR-3064-5p playing a crucial model and administered Fer-1 and in vivo siRNA targeting
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role in the restoration of BBB following damage. These PRDX6 to investigate the underlying mechanisms . The
findings highlight the potential of exosomal miR-3064-5p research confirmed Fer-1’s capacity to inhibit ferroptosis
as a treatment option for SAH, addressing BBB integrity and provide neuroprotection in SAH. SAH induction
and mitigating damage caused by SAH . resulted in reduced PRDX6 expression, which Fer-1
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ameliorated. Furthermore, Fer-1 effectively addressed
4.2. Inhibition of ferroptosis dysregulated lipid peroxidation, as indicated by glutathione
A study investigating the role of ferroptosis, an iron- and malondialdehyde levels, but this effect was reversed by
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dependent regulated cell death process, in SAH revealed si-PRDX6. Notably, the neuroprotective benefits of Fer-1
that the ferroptosis inhibitor, liproxstatin-1, effectively in SAH were compromised by PRDX6 knockdown and the
protected HT22 cells from hemin-induced damage by use of a calcium-independent phospholipase A2 (iPLA2)
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preserving mitochondrial function and mitigating lipid inhibitor . These findings underscore the involvement of
peroxidation. In in vivo experiments, characteristic PRDX6 in SAH-induced ferroptosis and its association
mitochondrial alterations in cortical neurons following SAH with Fer-1’s neuroprotective mechanism, particularly
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were demonstrated, and liproxstatin-1 treatment attenuated through its iPLA2 activity .
neurological deficits, brain edema, neuronal cell death, and 4.3. Nle DPhe -α-melanocyte-stimulating hormone
4
7
redox imbalance . Ferroptosis inhibition by liproxstatin-1
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was linked to the preservation of glutathione peroxidase 4 A study investigated the potential protective effects of
4
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and the down regulation of acyl-CoA synthetase long-chain the α-MSH analog Nle DPhe -α- melanocyte-stimulating
family member 4 and cyclooxygenase 2. Furthermore, hormone (NDP-MSH) in experimental SAH in rats. Initial
liproxstatin-1 reduced microglial activation and the release experiments demonstrated that intrathecal injection of low
of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), concentrations of NDP-MSH induced a tolerant phenotype
contributing valuable insights into SAH-related cell death in the basilar artery. Systemic treatment with NDP-MSH
mechanisms for future preclinical investigations . following SAH significantly reduced vasospasm on day 5.
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Transcript analysis revealed that SAH caused significant
NTN-1 was identified as a potent enhancer of peroxisome disruptions in the transcriptional profile of the basilar
proliferator-activated receptor gamma (PPARγ), a key artery, affecting genes related to inflammation, stress
transcription factor governing lipid metabolism. In the response, apoptosis, and vascular remodeling . NDP-
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context of NTN-1-mediated neuroprotection in SAH, MSH treatment mitigated most of these transcriptional
a study investigated ferroptosis, a recently identified changes and reduced the phosphorylation of extracellular-
form of cell death linked to lipid metabolism . The signal-regulated kinases (ERK1/2) and inhibitor protein
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results demonstrated that NTN-1 treatment significantly IκBα. These findings suggest that melanocortins, including
improved survival rates, increased neuron survival, and NDP-MSH, may serve as safe and effective therapeutic
enhanced neurological function, underscoring its role candidates for addressing SAH-related complications,
in inhibiting ferroptosis and mitigating neuron death. including vasospasm .
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NTN-1 treatment also upregulated the expression of 72
critical regulators of ferroptosis, including PPARγ, nuclear In a separate study , the aim was to investigate the
factor erythroid 2-related factor 2 (Nrf2), and glutathione potential of NDP-MSH in reducing oxidative stress and
neuronal apoptosis following ICH and to uncover the
peroxidase 4 (GPX4), thereby contributing to improved underlying mechanism. In a mouse ICH model, NDP-
neurological outcomes in SAH. These findings suggest MSH was administered intraperitoneally after ICH
that NTN-1 exerts neuroprotective effects by mitigating induction. The results revealed that NDP-MSH treatment
neuronal ferroptosis through the PPARγ/Nrf2/GPX4 and effectively mitigated neurological deficits, reduced brain
coenzyme Q10-ferroptosis suppressor protein 1 (CoQ10- water content, and inhibited oxidative stress and neuronal
FSP1) pathways, offering valuable insights into potential apoptosis 24 h after ICH . Furthermore, NDP-MSH
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therapeutic strategies for SAH-induced brain injury .
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administration promoted the expression of melanocortin-1
Peroxiredoxin 6 (PRDX6), a recognized antioxidant receptor (Mc1r), as well as the phosphorylation of PI3K,
protein, has been previously linked to ferroptosis and Akt, and Nrf2, leading to increased Bcl-2 expression and
lipid peroxidation, though its role in SAH remains elusive. decreased cleaved caspase-3 levels. Conversely, suppressing

Volume 7 Issue 2 (2024) 8 doi: 10.36922/itps.2019