A 2-oxa-spiro[5.4]decane scaffold displays neurotrophic, neurogenic and anti-neuroinflammatory activities with high potential for development as a versatile CNS therapeutic

Pranav Chintamani Joshi,Ramesh Samineni,Goverdhan Mehta,Arvind Kumar,Abhipradnya Bipin Wahul,Shailaja Karri,Srihari Pabbaraja,Dwaipayan Bhattacharya,Bommana Raghunath Reddy,Swati Maitra,Tapatee Das,Sumana Chakravarty,Lenin Veeraval

doi:10.1038/s41598-017-01297-z

Pranav Chintamani Joshi, Ramesh Samineni + Show 11 more

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https://doi.org/10.1038/s41598-017-01297-z

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Following our recent discovery of a new scaffold exhibiting significant neurotrophic and neurogenic activities, a structurally tweaked analogue, embodying a 2-oxa-spiro [5.4]decane framework, has been conceptualised and found to be more potent and versatile. It exhibits enhanced neurotrophic and neurogenic action in in vitro, ex vivo and in vivo models and also shows robust neuroprotection in mouse acute cerebral stroke model. The observed attributes are traceable to the predominant activation of the TrkB-PI3K-AKT-CREB pathway. In addition, it also exhibits remarkable anti-neuroinflammatory activity by concurrently down-regulating pro-inflammatory cytokines IL-1α and IL-6, thereby providing a unique molecule with a trinity of neuroactivities, i.e. neurotrophic, neurogenic and anti-inflammatory. The new chemical entity disclosed here has the potential to be advanced as a versatile therapeutic molecule to treat stroke, depression, and possibly other neuropsychiatric disorders associated with attenuated neurotrophic/ neurogenic activity, together with heightened neuroinflammation.

Highlights

One of the major global health care challenges today is to tackle debilitating neurological and psychiatric disorders that affect mood or emotion, and cognitive functions[1, 2]
Interventions to minimise and restore ischemia-induced neural damage[8, 9]. This is largely the case with diverse cognitive conditions mentioned above and there is hardly any new central nervous system (CNS) therapeutic introduced in recent decades to treat neurodegenerative conditions
#3 seems to have the potential to advance as a therapeutic molecule to treat stroke, depression and may be other neuropsychiatric disorders where neurotrophic and neurogenic activity is severely compromised and there is much neuroinflammation

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Introduction

One of the major global health care challenges today is to tackle debilitating neurological and psychiatric disorders that affect mood or emotion, and cognitive functions[1, 2]. The data analysis suggested that #3 was highly proneurogenic in ex vivo mouse neurosphere assay (Fig. 3A,B) at 0.01 μM concentration and showed significantly high rate of proliferation of NSCs/NPCs or neurogenesis than #4–#6 of the series, as well as the earlier reported spiro compound #215.

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