Carboxyamidotriazole

Sjögren's disease (SjD), a systemic autoimmune disease, suffers from restricted treatment choices. The activation of salivary gland epithelial cells and abnormal auto-reactive B cells, triggering cytokine and autoantibody generation, is key to its immunopathogenesis. Carboxyamidotriazole (CAI) was reported to have anti-inflammatory properties by reducing cytokines, yet its role in SjD was unknown. In this research, we targeted to probe CAI's potential treatment effect on SjD-like NOD/Ltj mice and its mechanism. Utilizing the salivary glands of these mice, we employed HE staining, ELISA, immunohistochemistry and flow cytometry. Findings revealed that CAI augmented salivary secretion, decreased water intake and serum autoantibody levels, suppressed histological alterations and lymphocyte foci, and diminished inflammatory factors such as IL-1β and IL-6. It also blocked IκBα degradation and p65 nuclear translocation. In vitro, CAI restrained IL-6 secretion from stimulated SGECs and halted Raji B cells' proliferation at G0/G1 stage. Overall, CAI shows an anti-SjD effect in NOD/Ltj mice, probably by regulating relevant cells and deactivating the NF-κB pathway.

Cerebral amyloid angiopathy (CAA) is a hallmark of Alzheimer's disease (AD), linked to adverse effects of emerging AD treatments. We explored the molecular effects of CAA in mouse brain and evaluated how these could be prevented by two repurposed United States Food and Drug Administration (FDA) approved treatments.

Brain proteomics was performed on the Tg‐SwDI genetic mouse model carrying disease causing mutations and developing AD characteristic cognitive deficits and severe CAA. Cortical and hippocampal tissues from presymptomatic male and female mice were studied.

We identify a core of dysregulated proteins across studies, including established markers of AD as well as proteins indicative of astrogliosis and negative regulators of synaptic stability and function. Two FDA approved, repurposed carbonic anhydrase inhibitors (CAIs), acetazolamide and methazolamide, were effective in preventing these molecular adaptations.

The two drugs broadly prevent proteome adaptations to the detrimental genotype and retain glutamatergic synapse proteins significantly closer to wild‐type levels.

The brain proteome changes of mice with CAA are mapped.Cortical and hippocampal tissues from presymptomatic male and female mice are studied.Markers of AD, astrogliosis, and synaptic stability are dysregulated.Two CAI are effective in preventing these protein changes.