A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury

Taheri, Ramezan Ali; Emami, Mahdi; Asadipour, Erfan; Kasirzadeh, Sara; Rouini, Mohammad-Reza; Najafi, Atabak; Heshmat, Ramin; Abdollahi, Mohammad; Mojtahedzadeh, Mojtaba

doi:10.1007/s00415-019-09366-1

Cited by 27 publications

(17 citation statements)

References 41 publications

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“…Metformin-associated lactic acidosis (MALA) has been recognized for several decades (54). However, the risk of MALA is still debated, and large clinical trials did not find it to cause lactic acidosis in patients with diabetes (55) or traumatic brain injury (56). In the cases reported, underlying comorbidities, such as renal failure or hypoxia could be the underlying cause (57).…”

Section: Discussionmentioning

confidence: 99%

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

Peralta¹,

Pinto²,

Arguello³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

Peralta¹,

Pinto²,

Arguello³

et al. 2020

JCI Insight

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“…A total of 1844 abstracts were excluded due to the following reasons: no study on TBI ( n = 785), no RCT ( n = 431), laboratory study ( n = 88), delayed intervention (e.g., study on rehabilitation techniques; n = 300), no original article ( n = 222), other reasons ( n = 18).During the further analysis of the 82 studies left, five studies had to be excluded, as the full-text revealed that the studies did not meet the criteria of RCTs; two more articles had to be excluded as the full-texts were only available in Russian/Chinese; three articles were identified as review articles. Therefore, a total of 72 articles [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58...…”

Section: Resultsmentioning

confidence: 99%

A Retrospective Analysis of Randomized Controlled Trials on Traumatic Brain Injury: Evaluation of CONSORT Item Adherence

et al. 2021

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Traumatic brain injury (TBI) contributes to death and disability, resulting in an enormous individual and socio-economic challenges. Despite huge efforts, there are still controversies on treatment strategies and early outcome estimation. We evaluate current randomized controlled trials (RCTs) on TBI according to their fulfillment of the CONSORT (Consolidated Statement of Reporting Trials) statement’s criteria as a marker of transparency and the quality of study planning and realization. A PubMed search for RCTs on TBI (January 2014–December 2019) was carried out. After screening of the abstracts (n = 1.926), the suitable full text manuscripts (n = 72) were assessed for the fulfillment of the CONSORT criteria. The mean ratio of consort statement fulfillment was 59% (±13%), 31% of the included studies (n = 22) complied with less than 50% of the CONSORT criteria. Citation frequency was moderately related to ratio of CONSORT item fulfillment (r = 0.4877; p < 0.0001) and citation frequency per year (r = 0.5249; p < 0.0001). The ratio of CONSORT criteria fulfillment was associated with the impact factor of the publishing journal (r = 0.6428; p < 0.0001). Essential data for study interpretation, such as sample size determination (item 7a), participant flow (item 13a) as well as losses and exclusions (item 13b), were only reported in 53%, 60% and 63%, respectively. Reporting and methodological aspects in RCTs on TBI still may be improved. Thus, the interpretation of study results may be hampered due to methodological weaknesses.

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“…Using a weight drop model of brain injury, Tao et al, demonstrated that metformin reduced microglial activation and the expression of pro-inflammatory cytokines, effects attributed to inhibiting NF-ĸB and p38 MAPK signaling ( Tao et al, 2018 ). A randomized clinical trial examining the safety and efficacy of metformin in severe TBI patients found that metformin treatment resulted in decreased serum levels of the astrocytic protein S100B, suggesting reduced neuronal injury ( Taheri et al, 2019 ). Taken together, these data suggest that metformin can restore mitochondrial function, reduce inflammation, offer axonal protection, and improve cognitive outcome after TBI, and supports its testing in persons at risk for repeat concussions such as athletes participating in contact sports and military personnel.…”

Section: Discussionmentioning

confidence: 99%

“…Metformin can also alter expression of a number of miRNAs involved in various cellular processes ( Alimoradi et al, 2021 ), and alter the gut microbiome ( Wu et al, 2017 ). Although metformin has been shown to reduce cell loss and improve cognitive outcome following moderate-to-severe TBI, it has not been examined whether metformin can reduce the pathophysiology of rmTBI in which overt damage is not observed ( Hill et al, 2016 ; Tao et al, 2018 ; Taheri et al, 2019 ; Rahimi et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Metformin Reduces Repeat Mild Concussive Injury Pathophysiology

Underwood

Redell

Maynard

et al. 2021

eNeuro

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Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain.Numerous cellular and molecular mechanisms underlying these pathological changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned if metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and cognitive functions were significantly improved when tested after discontinuation of the treatment. These studies suggest that metformin may be beneficial as a treatment for repeat concussion.Significance statement: Repeat concussions (or repeat mild traumatic brain injury, rmTBI) can occur in persons participating in contact sports, and in military personnel. Unfortunately, there are no approved treatments to lessen the consequences of rmTBI. It is thought that outcome from rmTBI is influenced by several secondary events, including altered brain metabolism, inflammation, and damage to brain cells. Here, we show that the anti-diabetes drug metformin reduces repeat concussion brain pathology and improves motor and cognitive functions.

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A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury

Cited by 27 publications

References 41 publications

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency

A Retrospective Analysis of Randomized Controlled Trials on Traumatic Brain Injury: Evaluation of CONSORT Item Adherence

Metformin Reduces Repeat Mild Concussive Injury Pathophysiology

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