Caspase-1 and Cathepsin B Inhibitors from Marine Invertebrates, Aiming at a Reduction in Neuroinflammation

Abstract

Neuroinflammation is a condition associated with several types of dementia, such as Alzheimer’s disease (AD), mainly caused by an inflammatory response to amyloid peptides that induce microglial activation, with subsequent cytokine release. Neuronal caspase-1 from inflammasome and cathepsin B are key enzymes mediating neuroinflammation in AD, therefore, revealing new molecules to modulate these enzymes may be an interesting approach to treat neurodegenerative diseases. In this study, we searched for new caspase-1 and cathepsin B inhibitors from five species of Brazilian marine invertebrates (four cnidarians and one echinoderm). The results show that the extract of the box jellyfish Chiropsalmus quadrumanus inhibits caspase-1. This extract was fractionated, and the products monitored for their inhibitory activity, until the obtention of a pure molecule, which was identified as trigonelline by mass spectrometry. Moreover, four extracts inhibit cathepsin B, and Exaiptasia diaphana was selected for subsequent fractionation and characterization, resulting in the identification of betaine as being responsible for the inhibitory action. Both molecules are already found in marine organisms, however, this is the first study showing a potent inhibitory effect on caspase-1 and cathepsin B activities. Therefore, these new prototypes can be considered for the enzyme inhibition and subsequent control of the neuroinflammation.

Exploring the mechanisms behind swimming performance limits to ocean warming and acidification in the Atlantic king scallop, Pecten maximus

“…The exact function of alkaloids in animals is not yet clear, but trigonelline is supposed to have various biological functions. In crustaceans urinary trigonelline was shown to serve as a chemical sensor for predator-prey interaction (Poulin et al, 2018) but it also to play a role in glucose metabolism and inflammation (see review of Anthoni et al, 1991;Mathur and Kamal, 2012;Moreno et al, 2022). In the hard clam, Mercenaria mercenaria, increased trigonelline levels were found after animals were exposed to hypersaline stress and were discussed as an oxidative stress response (Zhou et al, 2023).…”

Caspases in Alzheimer’s Disease: Mechanism of Activation, Role, and Potential Treatment

“…The authors managed to identify one extract, derived from Chiropsalmus quadrumanus , which possessed the activity of caspase-1 inhibition in enzymatic assays. Subsequent purification efforts led to the conclusion that trigonelline, an alkaloid commonly found in plants, could be the compound responsible for caspase inhibition [ 115 ].…”

Enzyme Inhibitors from Gorgonians and Soft Corals

“…Inhibitors for all major enzyme classes have been isolated and characterized from marine sources, including kinases [ 16 , 17 , 18 , 19 ], proteases [ 20 ], phospholipases [ 21 ], glucosidases [ 22 ], cholinesterases [ 23 , 24 ], topoisomerases [ 25 ], and DNA polymerases [ 26 ], among others. Accordingly, many of them have found interesting investigational, biomedical, and biotechnological applications [ 27 , 28 , 29 ]. The anthozoan sub-class Octocorallia, including over 3000 extant species of soft corals, gorgonian, and sea pens, has been considered a promising reservoir of unique natural products with unusual bioactivities [ 30 ].…”