Development of Novel Neuroprotective Strategies

The lab's research on development of novel neuroprotective strategies involves drug discovery techniques and application of clinical pharmacology methodologies directed at protecting the nervous system from direct and indirect inflammatory insults.

Systemic infections induce both fever and the production of catastrophic cytokine and chemokine storms, resulting in the infiltration of innate immune effector cells and molecules into the brain. These pathophysiological events increase intracellular calcium levels in neurons and trigger the consequent activation of calpain, a calcium-dependent protease, leading to neuronal injury and the development of cognitive deficits and seizures.

Dr. Howe's lab has discovered that ritonavir (Norvir), a prodrug commonly prescribed to people with HIV, exhibits a powerful neuroprotective effect in the lab's animal model of acute virus infection. Because ritonavir is exceptionally well-characterized in humans, Dr. Howe's research team anticipates that this research will accelerate translation of discovery experiments into clinical application.

Focus areas include:

  • Discovering the mechanisms of action for ritonavir and identifying the metabolic processes involved in converting the prodrug to a calpain-inhibitory metabolite
  • Synthesizing the calpain inhibitory metabolite and testing its neuroprotective efficacy
  • Testing the therapeutic relevance of calpain inhibitors in children with acute systemic infections and in diseases such as epilepsy that involve a currently untargeted neuroinflammatory component
  • Testing new behavioral analysis paradigms to uncover subtle cognitive deficits induced by inflammation and preserved by calpain inhibitors
  • Developing better multielectrodes for high-density measurement of mouse EEG
  • Creating new tools for analyzing mouse EEGs and quantifying neuroprotective effects on seizure biology in animal models of infection and injury
  • Discovering new pathways for drug delivery to the brain

Joel M. Reid, Ph.D., collaborates on this research.