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A Mouse Model for Vascular Cognitive Impairment and Dementia Based on Needle-guided Asymmetric Bilateral Common Carotid Artery Stenosis
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A Mouse Model for Vascular Cognitive Impairment and Dementia Based on Needle-guided Asymmetric Bilateral Common Carotid Artery Stenosis

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Soluble guanylyl cyclase: A novel target for the treatment of vascular cognitive impairment?

Ellis Nelissen1, Melissa Schepers2, Laura Ponsaerts3

  • 1Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.

Pharmacological Research
|October 26, 2023
PubMed

Insights

Vascular cognitive impairment (VCI) involves brain blood flow issues and damage. Soluble guanylate cyclase (sGC) modulation shows promise for treating VCI by reducing oxidative stress and inflammation.

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Pharmacology

Background:

  • Vascular cognitive impairment (VCI) is characterized by impaired cerebral blood flow (CBF), white matter lesions, endothelial dysfunction, and blood-brain barrier (BBB) issues.
  • Oxidative stress and inflammation are key molecular mechanisms underlying VCI pathology.
  • The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP pathway is crucial for vascular function but is impaired in pathological conditions.

Purpose of the Study:

  • To review the potential of targeting the NO-sGC-cGMP pathway, specifically sGC modulation, as a therapeutic strategy for VCI.
  • To explore the protective mechanisms of sGC agonists in the context of cerebrovascular dysfunction and neurodegeneration.
  • To highlight the under-researched role of sGC modulation in VCI pathology.

Main Methods:

  • Literature review focusing on the NO-sGC-cGMP pathway in cardiovascular diseases and VCI.
  • Analysis of molecular mechanisms involving sGC activity, oxidative stress, and inflammation.
  • Examination of existing sGC stimulators and activators and their potential application in VCI.

Main Results:

  • sGC exists in different forms (Fe(II)sGC, Fe(III)sGC, apo-sGC), with only the native Fe(II)sGC form being NO-sensitive.
  • Oxidized or heme-free sGC (Fe(III)sGC/apo-sGC) is inactive and can be targeted by sGC activators.
  • sGC agonists have demonstrated efficacy in cardiovascular diseases by reducing oxidative stress, inflammation, and improving vascular function.

Conclusions:

  • sGC modulation represents a promising therapeutic avenue for VCI, with potential to restore vascular and neural functions.
  • Further research is needed to investigate the specific protective mechanisms of sGC agonists in the cerebrovascular system and VCI.
  • Targeting sGC could offer a novel approach to combat the detrimental effects of oxidative stress and inflammation in VCI.

Keywords:
Blood-brain barrierCyclic nucleotidesDementiaGuanylyl cyclaseVascular cognitive impairment

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