Targeting Spermine Oxidase to Mitigate Traumatic Brain Injury Pathology in the Aging Brain

Area of Science:

• Neuroscience
• Biochemistry
• Gerontology

Background:

• Aging increases susceptibility to traumatic brain injury (TBI), leading to worse outcomes.
• Mechanisms underlying age-related TBI vulnerability, including oxidative stress and neuro-inflammation, are not fully understood.

Purpose of the Study:

• To identify molecular mechanisms linking aging, oxidative stress, neuro-inflammation, and TBI susceptibility.
• To investigate the role of spermine oxidase (SMOX) in age-dependent TBI outcomes.
• To evaluate SMOX inhibition as a therapeutic strategy for TBI in the elderly.

Main Methods:

• Utilized a mouse model of controlled cortical impact (CCI) to study TBI.
• Assessed SMOX expression, microglial activation, cytokine levels, and neuronal degeneration in aged versus young brains.
• Examined astrocytic glutamate transporter GLT-1 localization and function.
• Analyzed postmortem human brain samples and transcriptomic data for age-related SMOX changes.
• Pharmacologically inhibited SMOX using JNJ-9350 in aged mice and evaluated neurological and behavioral outcomes.

Main Results:

• SMOX expression was significantly upregulated in aged mouse brains post-TBI, particularly in neurons and microglia.
• Increased SMOX correlated with heightened microglial activation, pro-inflammatory cytokines, and neuronal degeneration.
• SMOX upregulation impaired astrocytic glutamate clearance via GLT-1 disruption, causing excitotoxicity.
• Human brain data confirmed age-related SMOX increases, supporting translational relevance.
• SMOX inhibition in aged mice reduced oxidative/inflammatory markers, preserved neurons, and improved motor, cognitive, and emotional functions post-TBI.

Conclusions:

• SMOX is a key mediator of age-related vulnerability to TBI, linking oxidative stress and neuro-inflammation.
• SMOX inhibition represents a promising therapeutic approach to mitigate TBI consequences in elderly individuals.