Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments, losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration

Rachmany, Lital; Tweedie, David; Rubovitch, Vardit; Li, Yazhou; Holloway, Harold W.; Kim, Do Kyung; Ratliff, Whitney A.; Saykally, Jessica N.; Citron, Bruce A.; Hoffer, Barry J.; Greig, Nigel H.; Pick, Chaim G.

doi:10.1038/s41598-017-03792-9

Cited by 42 publications

(31 citation statements)

References 77 publications

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“…Previous experiments involving our model of blast injury, at the same peak over-pressure, have yielded cognitive and behavioral changes in blast exposed mice similar to that TBI in humans at both acute and chronic timepoints, such as deficits in spatial and recognition memory and increased anxiety-like behavior 27,28 . One previous study also noted significant neurodegeneration within the neurons of the cortex and hippocampus at 3 days post-injury via FluoroJade B staining 29 .…”

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confidence: 79%

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Ratliff

Mervis

Citron

et al. 2020

Sci Rep

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Traumatic brain injury (TBI) has been designated as a signature injury of modern military conflicts. Blast trauma, in particular, has come to make up a significant portion of the TBIs which are sustained in warzones. Though most TBIs are mild, even mild TBI can induce long term effects, including cognitive and memory deficits. In our study, we utilized a mouse model of mild blast-related TBI (bTBI) to investigate TBI-induced changes within the cortex and hippocampus. We performed rapid Golgi staining on the layer IV and V pyramidal neurons of the parietal cortex and the CA1 basilar tree of the hippocampus and quantified dendritic branching and distribution. We found decreased dendritic branching within both the cortex and hippocampus in injured mice. Within parietal cortex, this decreased branching was most evident within the middle region, while outer and inner regions resembled that of control mice. This study provides important knowledge in the study of how the shockwave associated with a blast explosion impacts different brain regions. Brain trauma is one of the largest causes of death and disability in the United States, accounting for about 30% of all injury deaths 1. Traumatic brain injury (TBI) occurs when sufficient external force is imposed on the head resulting in brain damage. TBI varies in severity, with the most common form being mild (mTBI), which accounts for approximately 80% of the cases in the United States 2. While more severe TBI involve a mix of neuronal cell death and axonal degradation, mild TBIs can produce more subtle morphological changes within the cells of the brain and consequent cognitive deficits for which there are no consistently effective treatments. In addition to this, laboratory and clinical evaluations of mTBI patients (i.e. CT scan, MRI) often fail to reveal any clear and consistent morphological changes to the brain, thus making proper diagnosis difficult 3,4. Primary mechanical changes due to impact are generally followed by several biologic processes that occur in the minutes and days following mTBI 5 , resulting in secondary brain injuries, including inflammation in the brain, giving rise to elevated intracranial pressure 6. Physical symptoms of mTBI typically include headaches, nausea, dizziness and weakness; in addition to this there are a number of cognitive symptoms such as amnesia and problems with short term memory, as well as emotional symptoms such as depression or anxiety. Traumatic brain injury has become an increasingly common affliction among military personnel in recent conflicts. Among U.S. Forces, there have been approximately 384,000 brain injuries sustained since 2000 7. Blast-related TBIs make up a significant portion of these injuries 8,9 , accounting for numerous long term cognitive deficits in veterans who have been exposed to blasts. In the Iraq and Afghanistan wars, mTBI has been identified as a signature injury with an estimated 10-20% of veterans having been affected 10. In 2017, over 83,000 military personnel were diagnosed and treated for TBI ...

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confidence: 79%

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Ratliff

Mervis

Citron

et al. 2020

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“…Exendin-4 is an agonist of the glucagon-like peptide-1 receptor, which is currently prescribed for the treatment of type 2 diabetes and obesity 78 , 79 . However, several studies have also found its neuroprotective abilities in various models of neurological disorders 21 , 22 , 80 including a mouse model of blast-TBI 81 , 82 . In the current study, protective effects were shown in Exendin-4 treated rats with TBI at both 24 h and 6 weeks with similar effects to L-Carnitine on the cortex tissue and ameliorated neurological dysfunction and oxidative stress markers after the traumatic force.…”

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L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury

Chen

Chan

Linnane

et al. 2018

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There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.

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“…These methods have been described previously. [25][26][27][28][29] Elevated plus maze Anxiety level was assessed using the elevated plus maze for ICR mice 8 weeks following the final closed head injury. The apparatus consisted of two open arms and two closed arms which were enclosed on all sides with the roof open (30 x 15 x 5 cm).…”

Section: Mtbi and Transcription Factor Modulation 1911mentioning

confidence: 99%

Repetitive Mild Traumatic Brain Injury and Transcription Factor Modulation

Ratliff

Qubty

Delic

et al. 2020

Journal of Neurotrauma

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The worldwide incidence of traumatic brain injury (TBI) is *0.5% per year and the frequency is significantly higher among military personnel and athletes. Repetitive TBIs are associated with military and athletic activities, and typically involve more severe consequences. The majority of TBIs are mild; however, these still can result in long-term cognitive deficits, and there is currently no effective treatment. tert-Butylhydroquinone (tBHQ) and pioglitazone can activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-c) transcription factors, respectively, and each has been shown to be neuroprotective in various model systems. We examined behavioral and gene expression changes after repetitive mild TBI followed by simultaneous treatment with both factors. We used a repetitive closed head injury of mice involving five injuries with a 1-week interval between each TBI. We found that memory performance was significantly reduced by the injuries, unless the TBIs were followed by the tBHQ and pioglitazone administrations. Certain genes; for example, growth hormone and osteopontin, were downregulated by the injury, and this was reversed by the treatment, whereas other genes; for example, a tumor necrosis factor receptor, were upregulated by the injury and restored if the post-injury treatment was administered. Analysis of gene expression levels affected by the injury and/or the treatment point to potential mechanisms that could be exploited therapeutically.

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Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments, losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration

Cited by 42 publications

References 77 publications

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury

Repetitive Mild Traumatic Brain Injury and Transcription Factor Modulation

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