The role of amantadine in cognitive recovery early after traumatic brain injury: A systematic review

Role of the Dopaminergic System in the Striatum and Its Association With Functional Recovery or Rehabilitation After Brain Injury

“…The literature supports the beneficial effects of dopaminergic drugs in patients with TBI, confirming that they accelerate functional recovery and rehabilitation after brain injury ( Harmon and Boyeson, 1997 ; Bales et al, 2009 ; Frenette et al, 2011 , 2012 ; Osier and Dixon, 2016a ; Carrillo-Mora et al, 2017 ; Munakomi et al, 2017 ; Duong et al, 2018 ; Plummer et al, 2018 ; Loggini et al, 2020 ). The mechanisms of action of dopaminergic drugs administered to patients with TBI include blockade of the DA transporter (DAT), inhibition of DA reuptake and facilitation of DA synthesis, and the drugs most highly recommended by the Neurotrauma Foundation are methylphenidate (MPD), amantadine, and bromocriptine ( Bales et al, 2009 ).…”

“…In this context, imaging results in humans ( Donnemiller et al, 2000 ) have been consistent with western blot findings ( Wagner et al, 2005a , b ), indicating that striatal DAT levels are decreased after brain injury ( Wagner et al, 2005b ). However, DAT inhibitors including amphetamine ( Feeney et al, 1982 ; Hovda et al, 1987 ; Rau et al, 2016 ; Duong et al, 2018 ), MPD ( Kline et al, 1994 , Kaelin et al, 1996 , Kline et al, 2000 ; Arciniegas et al, 2002 ; Weber and Lütschg, 2002 ; Demarchi et al, 2005 ; Wagner et al, 2007 ; Wortzel and Arciniegas, 2012 ; Ekinci et al, 2017 ), and amantadine ( Arciniegas et al, 2002 ; Demarchi et al, 2005 ; Wu and Garmel, 2005 ; Wortzel and Arciniegas, 2012 ; Bleimeister et al, 2019 ; Okigbo et al, 2019 ; Loggini et al, 2020 ) have been used in animals and humans to evaluate the neuroprotective and symptomatic effects associated with improved recovery after brain injury. MPD and amantadine are clinically relevant treatments for TBI during the acute and chronic phases, including during the rehabilitative period ( Arciniegas et al, 2002 ; Demarchi et al, 2005 ; Warden et al, 2006 ; Bales et al, 2009 ).…”

“…The mechanisms of action of the dopaminergic drugs used to treat TBI have not been completely clarified, primarily because dopaminergic receptor activation may lead to restoration of neuronal circuits after injury in brain structures with high densities of these receptors. Dopaminergic abnormalities following TBI are clearly associated with functional disability in animals and humans ( Bales et al, 2009 ; Osier and Dixon, 2016a , b ; Jenkins et al, 2018 ; Traeger et al, 2020 ; Tsuda et al, 2020 ), and drugs with dopaminergic actions are beneficial for functional recovery after brain injury ( Meythaler et al, 2002 ; Matsuda et al, 2005 ; Frenette et al, 2012 ; Huang et al, 2014b ; Duong et al, 2018 ; Lan et al, 2019 ; Okigbo et al, 2019 ; Loggini et al, 2020 ). In the striatum, activation of D 1 Rs and D 2 Rs on MSNs is associated with increased and decreased excitability, respectively, in response to corticostriatal glutamatergic inputs ( Wickens and Wilson, 1998 ; Surmeier et al, 2007 ; Gerfen and Surmeier, 2011 ).…”

“…Evidence indicates that DA neurotransmission is disrupted following moderate and severe TBI, and benefits associated with dopaminergic system-affecting drugs have been reported ( Passler and Riggs, 2001 ; Meythaler et al, 2002 ; Sawyer et al, 2008 ; Bales et al, 2009 ; Jenkins et al, 2016 , 2018 ; Osier and Dixon, 2016a ; Lan et al, 2019 ). For example, administration of amantadine at 100–200 mg (twice a day) to patients with TBI appears to be beneficial in promoting intermediate-term cognitive recovery ( Loggini et al, 2020 ). Administration of methamphetamine, which is highly addictive and is of limited usefulness due to its potential for abuse and dependence, to patients with TBI improves Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) scores, whereas in injured rats, it improves motor and cognitive performance in a dose-dependent manner ( Duong et al, 2018 ).…”

Transcranial Low–Level Light Therapy: A New Hope for Preventing Cognitive Consequences of Traumatic Brain Injuries?

“…Adjuvant treatments with potential neuroprotective effects, such as the use of amantadine or progesterone in the early phases of recovery, have yielded mixed results in randomized clinical trials including patients with severe TBI. 4,5 Despite recent developments, the long-term follow-up of those who experienced a TBI suggests that there is still room for improvement. 6,7 If proven safe and effective, LLLT could reduce disabilities produced by TBI and improve outcomes from such rehabilitation programs.…”