Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Stroke presents a significant clinical challenge with limited acute treatment options.
• Neuroprotective agents targeting free radicals are under investigation.
• Nitrone compounds, like alpha-phenyl-N-tert-butylnitrone (PBN), show neuroprotection in animal stroke models.

Purpose of the Study:

• To evaluate the neuroprotective potential of disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) in stroke.
• To assess the efficacy of NXY-059 in preclinical stroke models, including primates.
• To determine if NXY-059's therapeutic mechanism involves free radical trapping.

Main Methods:

• Testing NXY-059 in rat models of transient and permanent focal ischemia.
• Evaluating NXY-059 in a primate model of permanent focal ischemia.
• Assessing NXY-059's radical trapping activity and its correlation with therapeutic effects.
• Monitoring tolerability and plasma concentrations in human stroke patients.

Main Results:

• NXY-059 demonstrated neuroprotection in rat models of focal ischemia.
• The compound improved neurological function and reduced infarct volume in a primate stroke model, even when administered hours post-occlusion.
• While NXY-059 exhibits radical trapping activity, this mechanism's contribution is debated.
• NXY-059 is well-tolerated in human stroke patients at effective concentrations.

Conclusions:

• NXY-059 is a promising neuroprotective agent for stroke, effective in various animal models.
• The compound achieves therapeutic plasma concentrations in humans and is well-tolerated.
• NXY-059 represents a potential first-in-class stroke therapeutic examined with validated preclinical exposure and timing.