Memantine Hydrochloride for Treatment of Cognitive Dysfunction Due to Traumatic Brain Injury

Overview

Posttraumatic consequences are common causes of disability and long-term morbidity. They include cognitive dysfunction, seizures, headache, dizziness, fatigue, sensory deficits, neurodegeneration and psychiatric disorders (e.g. posttraumatic stress disorder, depression, anxiety, etc). Diffuse axonal injury and disruption of normal neuronal function are the most common and important pathologic features of traumatic primary closed head injury. depression, anxiety, etc). Excitotoxicity and apoptosis caused by activation of N-methyl-D-aspartate (NMDA) glutamate receptors, are two main suggested mechanisms of traumatic neuronal cell death and posttraumtic neurologic adverse consequences. Experimental and clinical studies have demonstrated that memantine hydrochloride, NMDA-type glutamate receptor antagonist, could have beneficial effect in treatment of posttraumatic cognitive dysfunction. Memantine may contribute to cognitive improvements in TBI by decreasing the synaptic 'noise' resulting from excessive NMDA receptor activation, inhibition of β-amyloid mediated toxicity and readjustment of the balance between inhibition and excitation on neuronal networks in the central nervous system (CNS).

Posttraumatic consequences are common causes of disability and long-term morbidity. Traumatic brain injuries (TBIs) are traditionally classified into primary and secondary injuries. Primary brain injury is usually mechanically induced and occurs at the moment of injury while secondary injury is not mechanically induced, delayed from the moment of injury and may superimpose a previously injured brain by mechanical forces. Primary brain injury may be associated with focal scalp injury, skull fractures, brain contusion caused by contact (i.e. an object striking the head or the brain striking the inside of the skull) as well as diffuse axonal brain injury which is usually caused by acceleration-deceleration forces or rotational acceleration of the brain as a result of unrestricted movement of the head, shearing and tensile forces and compressive strains. Diffuse axonal injury and disruption of normal neuronal function are the most common and important pathologic features of TBI. The latter is mostly microscopic damage and is often not visible in neuroimaging. Consequences of TBI include cognitive dysfunction, seizures, headache, dizziness, fatigue, sensory deficits, neurodegeneration and psychiatric disorders (e.g. posttraumatic stress disorder, depression, anxiety, etc). Excitotoxicity and apoptosis are two main suggested mechanisms of traumatic neuronal cell death. The N-methyl-D-aspartate (NMDA) glutamate receptors are implicated in these mechanisms. Furthermore, the activation of NMDA receptors by glutamate promotes the production of reactive oxygen species (ROS) and nitric oxide (NO) which further exacerbate secondary cell injury. NMDA receptor plays a pivotal role in learning and memory. Experimental and clinical studies have demonstrated that memantine hydrochloride, NMDA-type glutamate receptor antagonist, could have beneficial effect in treatment of posttraumatic cognitive dysfunction. Memantine is an FDA-approved drug for the treatment of moderate to severe Alzheimer's disease and is also used clinically for the treatment of some patients with Parkinson's disease. Memantine is effective in blocking excessive activity of NMDA-type glutamate receptors and reduces the progression of dementia. Memantine has shown to be neuroprotective in animal models of cerebral and spinal cord ischemia and in models of TBI. Memantine may contribute to cognitive improvements in TBI by decreasing the synaptic 'noise' resulting from excessive NMDA receptor activation, inhibition of β-amyloid mediated toxicity and readjustment of the balance between inhibition and excitation on neuronal networks in the CNS. It showed beneficial effects in treating post-injury synaptic dysfunction in the neocortex, partially reversing deficits in long-term potentiation (LTP), mitigating pathologic NMDAR loss, and reducing tau phosphorylation and β-amyloid expression. Memantine spares hippocampal neurons after a single moderate/severe or repetitive TBI and normalizes LTP, β-amyloid and tau expressions, and neuroinflammation abnormalities in a repeat experimental model of TBI. In rodent studies, memantine dramatically increased adult hippocampal neurogenesis. Memantine does not have the significant negative side effects, such as hallucinations and coma of other NMDAR antagonists. High doses (≥20 mg/d) may cause non-serious side effects, e.g. dizziness, anxiety, restlessness or agitation,