Effects of Metal Exposure Prior to Traumatic Brain Injury on Memory and Cognition

Abstract

Traumatic brain injury (TBI) follows a set of complex pathological events linked with causing severe deficits in sensorimotor function, cognition, memory and personality. The primary injury is followed by secondary injury which contributes more to this impairment through activation of neurodegenerative and auto protective pathways. Heavy metals are known neurotoxicant causing cognitive and developmental deficits, where their chronic exposure at even low non-toxic doses ultimately triggers neurodgeneration. Aluminium (Al), Lead (Pb) and Arsenic (As) are among the most neurotoxicant metals with each causing significant neurological impairments on their own, however, due to their co-existence in the environment, their collective effect on living organisms is altered. Therapies for TBI are developed on controlled model with no previous exposure of neurotoxic metals. We hypothesize that the degenerative effects on nervous system produced by chronic environmental exposure of metals alters the neurophysiological outcome after traumatic brain injury. This study aims to evaluate the effects caused by chronic exposure of metals before the incidence of traumatic brain injury on sensorimotor function, cognition and memory in mice. 8 week old male BALB/c mice were divided into six groups (n=12 each group): Group 1(Control), Group 2 (TBI), Group 3 (TBI + Aluminium 20 mg/kg), Group 4 (TBI + Lead 20 mg/kg), Group 5 (TBI + Arsenic 20 mg/kg) and Group 6 (TBI + Al (20 mg/kg) + Pb (20 mg/kg) + As (20 mg/kg)). Each metal at 20 mg/kg was administered in drinking water for 6 weeks after which close head trauma was induced by weight drop model. Recovery of sensorimotor function from trauma was evaluated by measuring neurological severity score at 4h, 24h, 48h and 120h post- injury. Cognitive abilities and memory evaluation was done by performing Morris water maze test, novel object recognition, fear conditioning and context while levels of anxiety and activity were measured by observing the behavior of mice in elevated plus maze and open field test. Behavioral analysis suggests that Al, Pb and As on combined exposure generally act together to potentiate the neurological impairing effects of TBI and develop more pronounced deficits in motor function, spatial, object based, fear and context memory while also stimulating anxiety like behavior in mice. Conversely, certain tests propose that each of these metals might act differently on brain, where one metal suppresses the brain damaging activity of the other. However, In-vitro verification of these results and further evaluation of the neurodegenerative effects of combined metal exposure and TBI is required to better understand the realistic outcome of TBI and accordingly develop its therapeutic regime.