Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138✰

Vogelaar, P.; Nakladal, D; Swart, Daniël H.; Tkáčiková, Ľudmila; Tkáčiková, Soňa; Graaf, Adrianus Cornelis van der; Henning, Robert H.; Krenning, Guido

doi:10.1016/j.ejps.2021.106033

Cited by 5 publications

(6 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The efficacy of SUL-138 in preserving mitochondrial function, preventing endothelial cell death, and AKI in the pre-clinical models combined with the favourable safety profile from pre-clinical studies make SUL-138 a promising compound to avert organ injury in patients with sepsis [ 19 , 37 ]. However, several limitations have to be taken into account, as well as patient factors that may affect the efficacy and safety of the drug in human sepsis.…”

Section: Discussionmentioning

confidence: 99%

“…Given these actions, we hypothesized that SUL compounds preserve mitochondrial function during sepsis, thus preventing organ damage. In this study, we employ the (S)-enantiomer SUL-138, as this compound encompasses a favourable pharmacokinetic profile, and a favourable safety profile indicated by absence of carcinogenicity and genotoxicity [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

Star

Slikke

Buiten

et al. 2023

IJMS

View full text Add to dashboard Cite

Sepsis is defined as a dysregulated host response leading to organ dysfunction, which may ultimately result in the patient’s death. Mitochondrial dysfunction plays a key role in developing organ dysfunction in sepsis. In this study, we explored the efficacy of the novel mitochondrial protective compound, SUL-138, in sepsis models in HUVECs and mice. In LPS-challenged HUVECs, SUL-138 preserved mitochondrial membrane potential and oxygen consumption and limited mitochondrial oxidative stress, resulting in increased survival at 48 h. Further, SUL-138 dampened the LPS-induced expression of IL-1β, but not of NLRP3, and IL-18 in HUVECs. Sepsis in mice induced by cecal ligation and puncture (CLP) led to a lower mitochondrial membrane potential and increased levels of mitochondrial oxidative stress in the kidney, which SUL-138 limited. In addition, SUL-138 mitigated the CLP-induced increase in kidney dysfunction markers NGAL and urea. It dampened the rise in kidney expression of IL-6, IL-1β, and ICAM-1, but not TNF-α and E-selectin. Yet, SUL-138 limited the increase in plasma levels of IL-6 and TNF-α of CLP mice. These results demonstrate that SUL-138 supports mitochondrial function, resulting in a limitation of systemic inflammation and preservation of kidney function.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

Star

Slikke

Buiten

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…The SUL-138-evoked long-term metabolic adaptations in mitochondria, and its effects on synaptic transmission and memory performance, illustrate that targeting mitochondrial bioenergetics might be a promising strategy to prevent cognitive impairment in AD. Interestingly, SUL-138 supports complex I and IV activity without affecting basal mitochondrial membrane potential or causing apparent mitochondrial toxicity [ 136 ]. Moreover, hibernation-inspired 6-chromanols prevent organ damage in various preclinical models of conditions or diseases with impaired mitochondrial function, including whole body cooling [ 137 ], renal ischemia/reperfusion [ 136 ], COPD [ 138 , 139 ], and diabetes [ 140 ].…”

Section: Hibernation-derived Mechanisms Of Mitochondrial Targeting: I...mentioning

confidence: 99%

Mitochondrial Targeting against Alzheimer’s Disease: Lessons from Hibernation

de Veij Mestdagh,

Smit,

Henning

et al. 2023

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.

show abstract

“…These changes coincide with extensive structural and functional neuronal plasticity in the hippocampus, ranging from changes in synaptic plasticity during daily torpor in mice to complete dendritic retraction and restoration in seasonal hibernators [13][14][15][16][17][18]. Inspired by the effects of hibernation on mitochondria, and the associated boost in neuronal plasticity, 6-chromanol derived small molecules were developed that mimic the action of endogenous mediators conferring organ protection in hibernation [19][20][21] by phenotypical screening of cooled and rewarmed cells [22]. Follow-up research demonstrated the 6-chromanol derivatives, including SUL-138, to preserve mitochondrial respiratory chain function by supporting complexes I and IV function, thereby preventing ROS formation while stimulating ATP production [23].…”

Section: Introductionmentioning

confidence: 99%

“…SUL-138 does so without affecting basal mitochondrial membrane potential or causing apparent mitochondrial toxicity. Moreover, 6-chromanols preclude organ damage in various preclinical models of conditions or diseases with impaired mitochondrial function, including whole body cooling [24], renal ischemia/reperfusion [22], COPD [25,26], and diabetes [27]. Lastly, SUL-138 is able to pass the blood-brain-barrier.…”

Section: Introductionmentioning

confidence: 99%

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

et al. 2022

View full text Add to dashboard Cite

Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Methods Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. Results SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Conclusion Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression.

show abstract

Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138✰

Cited by 5 publications

References 41 publications

The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

Mitochondrial Targeting against Alzheimer’s Disease: Lessons from Hibernation

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Contact Info

Product

Resources

About