Konar, A. | bioRxiv Science

bioRxiv2022

Preclinical efficacy of bacosides-lauric acid nano-herbal formulation incomparison to rivastigmine for treatment of Alzheimer's disease

Despite decades of rigorous scientific endeavors for Alzheimers disease (AD) drug development, massive failures in clinical trials is continuously posing healthcare and societal burden. Currently recommended single targeted drugs including rivastigmine with limited bioavailability can alleviate AD symptoms only for a limited period of time but unable to reverse the disease progression. Recent evidences consider poly-pharmacological and multi-targeted agents aiming at amyloid and tau burden, neuroinflammation, neuroprotection and cognitive enhancement as potential treatment options. In this regard, bioactive herbal compounds with holistic action and minimal adversities have gained prominence, though lacunae in their scientific validation and limited bio-permeability to cross BBB represent major hurdles. Previously, we showed that lactoferrin conjugated PEG-S-S-PLA-PCL-OH efficaciously delivered herbal compounds to brain and such nano-herbal formulation of bacosides-lauric acid (BAN-LAN) attenuated neuronal damages induced by scopolamine in vitro. Here, we tested the preclinical potential of BAN-LAN in reversal of AD pathologies in 5XFAD transgenic mice. Our nano-herbal formulation substantially reduced amyloid burden by clearing A{beta} plaques in the hippocampus of 5XFAD mice and also attenuated a{beta}42 induced alterations in AD associated gene expression in hippocampal neurons in vitro. It showed neuroprotection by rescuing neuronal damage and promoting neurogenesis in the hippocampus of AD transgenic mice. Anti-neuroinflammatory properties were also exhibited by the formulation as evident from inhibition of hippocampal astrocytic and microglial activation in 5XFAD mice. BAN-LAN showed cognitive efficacy by restoring memory impairment in AD transgenic mice and effects were more pronounced than unconjugated natural form and rivastigmine. These findings suggest that BAN-LAN may serve as a promising therapeutic agent for AD with better brain penetration and targeting multiple AD pathways.

pharmacology and toxicology↗

bioRxiv2021

Early life trauma leads to violent behavior and its inheritance by impairing local thyroid hormone availability in brain

Escalated and inappropriate levels of aggressive behavior referred to as pathological in psychiatry can lead to violent outcomes with detrimental impact on health and society. Early life trauma triggers adulthood violence and criminality, though molecular mechanisms remain elusive. Here, we provide prefrontal cortex and hypothalamus specific transcriptome profiles of peripubertal stress (PPS) exposed Balb/c adult male mice exhibiting escalated aggression and adult female mice resilient to such aberrant behavioral responses. We identify transthyretin (TTR) as a key regulator of PPS induced escalated aggression and its intergenerational inheritance. TTR mediated long-term perturbation in hypothalamic thyroid hormone (TH) availability contributed to male aggressive behavior without affecting circulating hormone. Ttr gene ablation in hypothalamus impaired local TH signaling including levels of TH transporters (Mct8, Oatp1c1), deiodinase 2(DIO2) and TH responsive genes (Nrgn, Trh and Hr). Escalated aggressive behavior and impaired TTR-TH signaling was also inherited in F1 male progenies. Further, we deciphered Ttr promoter hyper methylation in hypothalamus of such abnormally aggressive males across generations. Interestingly prefrontal cortex showed opposite pattern of Ttr expression as well as long term epigenetic changes. Also, T4 increase by levothyroxine in PFC did not produce any behavioral changes. Our findings reveal that trauma during puberty trigger lasting escalated aggression by epigenetic programming of TTR and consequent impaired thyroid availability in brain. TTR-TH signaling in brain can serve as potential target in reversal of escalated aggression and related psychopathologies.

neuroscience↗