Abstract
Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer’s disease. In this study, we evaluated the effect of four newly synthesized pyrrolo[3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia worldwide and the most frequent neurodegenerative disease in the elderly
It is widely accepted that inflammatory reactions and oxidative stress play an important role in the pathomechanism of AD, and the main pathological determinant of this disease is the accumulation of β-amyloid (Aβ) deposits within the brain [3,4,5]
The continuous activation of microglia affects the induction of immune response receptors, including Toll-like receptors (TLRs), causing inflammation [8,9]
Summary
Alzheimer’s disease (AD) is the most common form of dementia worldwide and the most frequent neurodegenerative disease in the elderly. It involves the progressive and irreversible loss of nerve cells in various brain zones, in particular, the hippocampus and cortex. It is widely accepted that inflammatory reactions and oxidative stress play an important role in the pathomechanism of AD, and the main pathological determinant of this disease is the accumulation of β-amyloid (Aβ) deposits within the brain [3,4,5]. There is much evidence that people with Alzheimer’s disease have much microglia in their brains that causes chronic inflammation. Increased expression of proinflammatory mediators such as cytokines and chemokines (IL-1β, IL-6, TNF-α), complement components (C1q, C3a, C3b), and acute-phase proteins opsonising β-amyloid deposits are observed [10]
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