Technologies

A family of pyridazine compounds that modulate intracranial inflammatory responses following CNS insults such as diverse pathogenic stimuli, physical force trauma, brain hemorrhage, or complications of major surgeries. #therapeutics #CNS #smallmolecule

Northwestern researchers have developed a family of pyridazine compounds that modulate intracranial inflammatory responses following CNS insults such as diverse pathogenic stimuli, physical force trauma, brain hemorrhage, or complications of major surgeries. Proinflammatory mediators are known to contribute to pathologic processes including cerebral edema, long-term neuronal dysfunction and cognitive impairment. Therefore, preserving neurons during such proinflammatory processes would improve neurocognitive outcomes and enhance quality of life in affected individuals. The team of researchers have shown that these pyridazine compounds are able to suppress cytokine induction from activated microglia in culture like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte-chemoattractant factor (MCP-1), and interleukin-6 (IL-6). These compounds were tested in three established rodent models of chronic neuroinflammatory diseases: (1) an amyloid beta infusion model of Alzheimer's Disease; (2) a closed-head injury model of traumatic brain injury; and (3) a clostridial collagenase-induced intracerebral hemorrhage model. In these models, they confirmed that treatment with the pyridazine compounds results in a significant reduction in cerebral edema and a remarkable improvement in both motor skills and neurocognitive outcomes. In addition, histological and biochemical studies show reduced hippocampal glial activation, strongly suggesting an in vivo reduction in neuroinflammation. These results serve as potential indications for these compounds. IND enablement studies showed no toxicology with a consistent pharmacokinetic profile across wide range of doses in different species and healthy humans.