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

Summary

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).

Timeline

Start

2024-01-01

Primary completion

2024-06-01

Completion

2024-08-01

Publications

• Background Bramlett HM, Dietrich WD. Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes. J Neurotrauma. 2015 Dec 1;32(23):1834-48. doi: 10.1089/neu.2014.3352. Epub 2014 Dec 19.
• Background Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015 May;15(5):27. doi: 10.1007/s11910-015-0545-1.
• Background Effgen GB, Morrison B 3rd. Memantine Reduced Cell Death, Astrogliosis, and Functional Deficits in an in vitro Model of Repetitive Mild Traumatic Brain Injury. J Neurotrauma. 2017 Feb 15;34(4):934-942. doi: 10.1089/neu.2016.4528. Epub 2016 Aug 8.
• Background Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010 Sep;113(3):564-70. doi: 10.3171/2009.12.JNS09689.
• Background Girouard H, Wang G, Gallo EF, Anrather J, Zhou P, Pickel VM, Iadecola C. NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci. 2009 Feb 25;29(8):2545-52. doi: 10.1523/JNEUROSCI.0133-09.2009.
• Background Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845-8. doi: 10.1126/science.284.5421.1845.
• Background Lipton SA. The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res. 2005 Apr;2(2):155-65. doi: 10.2174/1567205053585846.
• Background Chen HS, Wang YF, Rayudu PV, Edgecomb P, Neill JC, Segal MM, Lipton SA, Jensen FE. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience. 1998 Oct;86(4):1121-32. doi: 10.1016/s0306-4522(98)00163-8.
• Background Dogan A, Eras MA, Rao VL, Dempsey RJ. Protective effects of memantine against ischemia-reperfusion injury in spontaneously hypertensive rats. Acta Neurochir (Wien). 1999;141(10):1107-13. doi: 10.1007/s007010050491.
• Background Mei Z, Qiu J, Alcon S, Hashim J, Rotenberg A, Sun Y, Meehan WP 3rd, Mannix R. Memantine improves outcomes after repetitive traumatic brain injury. Behav Brain Res. 2018 Mar 15;340:195-204. doi: 10.1016/j.bbr.2017.04.017. Epub 2017 Apr 13.

Drugs

Indications

No indication recorded.