Beyond Acute Traumatic Brain Injury: Molecular Implications of Associated Neuroinflammation in Higher-Order Cognitive Processes

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury

“…As it was described before, working memory is one of the cognitive domains primarily affected by TBI that could predict patient’s outcome ( Ricker et al, 2001 ; Wylie et al, 2015 ; Montivero et al, 2021 ). In preclinical studies, an individual with normal working memory will remember the arms of the Y-maze that it has already visited and will show a tendency to enter the less recently visited arm.…”

“…The secondary injuries appear immediately after trauma and may last for long periods ( Nortje and Menon, 2004 ; Pearn et al, 2017 ). They are frequently associated with ischemia, brain edema, and neuroinflammation, and may take place in a period from days to weeks, or even months, triggering a complex cascade of intracellular signaling, which include ATP depletion, mitochondrial dysfunction, oxidative stress (OS), and cytoskeleton damage ( Montivero et al, 2021 ). In turn, those events induce the production of toxic and pro-inflammatory mediators, such as prostaglandins, oxidative metabolites, chemokines, and proinflammatory cytokines, which can lead to lipid peroxidation, protein oxidation, enhanced blood brain barrier (BBB) disruption and brain edema to finally induce neuronal dysfunction or death ( Krishnamurthy et al, 2016 ; Pearn et al, 2017 ).…”

“…It has been described that secondary injury mechanisms, as outlined above, may contribute to the cognitive deficits observed even long-term after injury. Individuals suffering from TBI of any severity could experience a cluster of symptoms for a prolonged period of time ( Kushner, 1998 ; Ryan and Warden, 2003 ; McMahon et al, 2014 ; Stocchetti and Zanier, 2016 ), commonly recognized as post-concussive syndrome (PCS) ( Alexander, 1995 ; Ryan and Warden, 2003 ; Stocchetti and Zanier, 2016 ; Montivero et al, 2021 ). The PCS includes a variety of symptoms ranging from cognitive symptoms (speech changes, attention loss, dysfunction in executive function and memory, or mental slowing, among others) Kaplan et al (2018) ; physical and somatic symptoms (hearing and visual disturbances, sensitivity to light or sound, pain, headaches, dizziness, nausea, fatigue, sleep disruption, and even seizures) ( Lozano et al, 2015 ; Webster et al, 2017 ; Kaplan et al, 2018 ; Wolfe et al, 2018 ) and emotional/behavioral symptoms (executive dysfunction, anxiety, irritability, depression, and attention deficit) ( Arciniegas et al, 2005 ; Bryan, 2013 ; Paterno et al, 2017 ).…”

“…Regretfully, it is difficult to identify those individuals at risk for PCS with the standard clinical assessment used. Nevertheless, since the working memory is one of the cognitive functions primarily affected by TBI, its clinical evaluation, including functional magnetic resonance imaging performed within the first week of injury, may contribute to predicting the patients´ outcome ( Christodoulou et al, 2001 ; Ricker et al, 2001 ; Hillary et al, 2011 ; Wylie et al, 2015 ; Montivero et al, 2021 ).…”