Treventis (Canada)

Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes. To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing. We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound. This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.

Vascular dementia (VaD) is well recognized as the second most familiar form of dementia in the aged population. The present study is aimed to investigate the neuroprotective effects of ethanolic extract of leaves of Ocimum sanctum (EEOS) against hyperhomocysteinemia (HHcy)-induced vascular dementia (VaD) in Wistar rats. HHcy was induced by administering L-methionine (1.7g/kg, p.o) for 4weeks. Donepezil (0.1 mg/kg, p.o.) and EEOS (100mg/kg, 200mg/kg, 400mg/kg, p.o.) were administered from the 14th day of L-methionine treatment. The behavioral impairment caused due to HHcy in rats was assessed by the Morris water maze (MWM) and Y-maze tests using a video tracking system. Biochemical estimations and aortic ring assay were also performed followed by a molecular docking analysis of active chemical constituents present in the leaves of Ocimum sanctum Linn. In this study, the EEOS treatment in hyperhomocysteinemic rats has showed significant improvement in spatial learning and working memory performance. The EEOS treatment further increased nitric oxide bioavailability and significantly altered all serum and brain biochemical parameters in a dose-dependent manner. The docking analysis revealed that among all the phytoconstituents of Ocimum sanctum compound (IX), molludistin has showed good inhibitory activity against S-adenosyl homocysteine, thus preventing homocysteine formation and may be responsible for potential effects of EEOS against HHcy-induced VaD. From our results, we conclude that EEOS can be used as a promising adjunct therapy for treatment of HHcy-induced VaD and oxidative stress.

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