Characterization of Novel Src Family Kinase Inhibitors to Attenuate Microgliosis
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Published on: September 16, 2019
Gunjan D Manocha1, Kendra L Puig1, Susan A Austin2
1Department of Basic Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND, 58203, United States of America.
Abstract:
Microgliosis is a major hallmark of Alzheimer's disease (AD) brain pathology. Aβ peptide is hypothesized to act as a stimulus for microglia leading to activation of non-receptor tyrosine kinases and subsequent secretion of pro-inflammatory cytokines. Therefore, the signaling pathways mediating microglial activation may be important therapeutic targets of anti-inflammatory therapy for AD. Four novel compounds were chosen after high throughput screening kinase activity assays determined them as potential Lyn kinase inhibitors. Their kinase inhibitory and anti-inflammatory effect on Aβ-stimulated activation was assessed using the murine microglial cell line, BV2. Cells were treated with the compounds to determine effects on active, phosphorylated levels of Src family kinases, Src and Lyn, as well as MAP kinases ERK, JNK and p38. Only one compound, LDDN-0003499, produced a dose dependent decrease in basal levels of active, phosphorylated Src and Lyn in the BV2 cells. LDDN-0003499 treatment also attenuated the Aβ-stimulated increase in active, phosphorylated levels of Lyn/Src and TNFα and IL-6 secretion. This study identifies a novel small molecule Src family tyrosine kinase inhibitor with anti-inflammatory effects in response to Aβ stimulation of microglia. Further in vitro/in vivo characterization of LDDN-0003499 as well as structural modification may provide a new tool for attenuating microglial-mediated brain inflammatory conditions such as that occurring in AD.
Insights
Researchers identified a novel compound, LDDN-0003499, that inhibits Lyn kinase activity. This compound reduces inflammation in microglia stimulated by amyloid-beta, offering potential for Alzheimer's disease therapy.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microgliosis, driven by microglia activation, is a key feature of Alzheimer's disease (AD) pathology.
- Amyloid-beta (Aβ) peptides stimulate microglia, activating kinases and promoting pro-inflammatory cytokine release.
- Targeting microglial signaling pathways offers a therapeutic strategy for AD's neuroinflammation.
Purpose of the Study:
- To identify novel small molecules inhibiting Lyn kinase activity.
- To evaluate the anti-inflammatory effects of potential Lyn kinase inhibitors on Aβ-stimulated microglia.
- To assess the impact of these compounds on Src family kinases and pro-inflammatory cytokine secretion.
Main Methods:
- High-throughput screening identified four potential Lyn kinase inhibitors.
- Murine microglial cell line (BV2) was used to assess kinase inhibitory and anti-inflammatory effects.
- Western blotting measured phosphorylated Src family kinases (Src, Lyn) and MAP kinases (ERK, JNK, p38).
- Cytokine levels (TNFα, IL-6) were quantified via ELISA.
Main Results:
- One compound, LDDN-0003499, demonstrated a dose-dependent reduction in basal active Src and Lyn levels.
- LDDN-0003499 treatment significantly attenuated Aβ-induced increases in active Lyn/Src and secretion of TNFα and IL-6.
- This compound selectively inhibited Src family tyrosine kinases in Aβ-stimulated microglia.
Conclusions:
- LDDN-0003499 is a novel small molecule inhibitor of Src family tyrosine kinases.
- The compound exhibits anti-inflammatory properties by reducing microglial activation and cytokine release in response to Aβ.
- Further research and structural modifications of LDDN-0003499 may lead to new treatments for neuroinflammatory conditions like AD.
