A Multitarget Approach against Neuroinflammation: Alkyl Substituted Coumarins as Inhibitors of Enzymes Involved in Neurodegeneration.
Emanuela BerrinoSimone CarradoriFabrizio CartaFrancesco MelfiMarialucia GalloriniGiulio PoliTiziano TuccinardiJosé G Fernández-BolañosÓscar LópezJacobus P PetzerAnél PetzerPaolo GuglielmiDaniela SecciClaudiu T SupuranPublished in: Antioxidants (Basel, Switzerland) (2023)
Neurodegenerative disorders (NDs) include a large range of diseases characterized by neural dysfunction with a multifactorial etiology. The most common NDs are Alzheimer's disease and Parkinson's disease, in which cholinergic and dopaminergic systems are impaired, respectively. Despite different brain regions being affected, oxidative stress and inflammation were found to be common triggers in the pathogenesis and progression of both diseases. By taking advantage of a multi-target approach, in this work we explored alkyl substituted coumarins as neuroprotective agents, capable to reduce oxidative stress and inflammation by inhibiting enzymes involved in neurodegeneration, among which are Carbonic Anhydrases (CAs), Monoamine Oxidases (MAOs), and Cholinesterases (ChEs). The compounds were synthesized and profiled against the three targeted enzymes. The binding mode of the most promising compounds ( 7 and 9 ) within MAO-A and -B was analyzed through molecular modeling studies, providing and explanation for the different selectivities observed for the MAO isoforms. In vitro biological studies using LPS-stimulated rat astrocytes showed that some compounds were able to counteract the oxidative stress-induced neuroinflammation and hamper interleukin-6 secretion, confirming the success of this multitarget approach.
Keyphrases
- oxidative stress
- cerebral ischemia
- diabetic rats
- dna damage
- ischemia reperfusion injury
- induced apoptosis
- lipopolysaccharide induced
- traumatic brain injury
- molecular docking
- ionic liquid
- lps induced
- inflammatory response
- crispr cas
- cognitive impairment
- case control
- signaling pathway
- subarachnoid hemorrhage
- cognitive decline
- white matter
- anti inflammatory
- genome editing
- transcription factor
- brain injury
- mild cognitive impairment
- drug delivery
- dna binding
- cancer therapy
- visible light
- heat shock protein