👤 Aditya Dandekar

Post-traumatic stress disorder (PTSD) is a stressful mental illness that arises after exposure to unforeseen traumatic events. The majority of PTSD cases are often refractory to pharmacological interventions. Herein, considering the neuroprotective effects of quercetin and chitosan in several brain disorders, we examined the effect of quercetin-loaded chitosan nanoparticles (QCNPs), administered via nose-to-brain delivery, on PTSD-like phenotypes in mice. QCNPs were synthesized using the ethanol injection method. We observed uniform spherical structure and 120-170 nm diameter of nanoparticles in transmission-electron microscopy analysis. The polydispersity index, zeta potential, and entrapment efficiency were 0.36 ± 0.0104, 39.05 mV, and 81.86 ± 1.60 %, respectively. Male C57BL/6 mice subjected to controlled-cortical impact (CCI) surgery followed by single-prolonged stress (SPS) exhibited PTSD-like symptoms, including deficits in sociability, anxiety and cognition. The CCI + SPS-driven neurobehavioral dysfunctions related to sociability index, anxiety-like phenotype, and cognition were evaluated employing social-approach social avoidance (SASA), elevated zero maze (EZM), Y-maze, and novel object recognition task (NORT). Intranasal delivery of QCNPs, at 0.06 mg/kg of body weight for 14 days, ameliorated CCI + SPS-generated PTSD-like behaviors in mice. The depleted levels of postsynaptic-density protein 95 (PSD-95), brain-derived neurotrophic factor (BDNF), and doublecortin in the hippocampus of CCI + SPS-exposed mice were restored following QCNPs treatment. Moreover, QCNPs administration reduced the expression of astrocyte marker glial-fibrillary acidic protein (GFAP), IBA-1, c-Fos, and proinflammatory cytokines (C-reactive protein, IL-6, TNF-α, and IL-1β) in the hippocampus of CCI + SPS group. These results suggest that nose-to-brain delivery of QCNPs reverses CCI + SPS-generated PTSD-like phenotypes by modulating neuroinflammatory mediators and enhancing neuronal and synaptic proteins. Show less

Bacterial endotoxin can induce inflammatory and metabolic changes in the host. In this study, we revealed a molecular mechanism by which a stress-inducible, liver-enriched transcription factor, cAMP-responsive element-binding protein hepatic-specific (CREBH), modulates lipid profiles to protect the liver from injuries upon the bacterial endotoxin lipopolysaccharide (LPS). LPS challenge can activate CREBH in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. Upon LPS challenge, CREBH interacts with TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that functions as a key mediator of TLR signaling, and this interaction relies on MyD88. Further analysis demonstrated that TRAF6 mediates K63-linked ubiquitination of CREBH to facilitate CREBH cleavage and activation. CREBH directly activates expression of the gene encoding Apolipoprotein A4 (ApoA4) under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animals. CREBH deficiency led to reduced production of circulating HDL and increased liver damage upon high-dose LPS challenge. Therefore, TLR/MyD88-dependent, TRAF6-facilitated CREBH activation represents a mammalian hepatic defense response to bacterial endotoxin by modulating HDL. Show less

Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder. Show less