Guanosine Protects Against Traumatic Brain Injury-Induced Functional Impairments and Neuronal Loss by Modulating Excitotoxicity, Mitochondrial Dysfunction, and Inflammation

Gerbatin, Rogério da Rosa; Cassol, Gustavo; Dobrachinski, Fernando; Ferreira, Ana Paula Oliveira; Quines, Caroline Brandão; Pace, I. D. Della; Busanello, Guilherme L.; Gutierres, Jessié Martins; Nogueira, Cristina W.; Oliveira, Mauro Schneider; Soares, Félix Alexandre Antunes; Morsch, Vera Maria; Fighera, Michele Rechia; Royes, Luiz Fernando Freire

doi:10.1007/s12035-016-0238-z

Cited by 38 publications

(19 citation statements)

References 62 publications

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“…A single injection of guanosine (7.5 mg/kg i.p.) administered 40 min after LFPI in adult Wistar rats improved the motor impairment 8hours after injury as well as reduced the ipsilateral cortical injury, glutamate uptake, Na+/K+-ATPase, glutamine synthetase activity, alterations in mitochondrial function, neuronal death, inflammation and brain edema (Gerbatin et al, 2017). This study did not assess the antiepileptogenic potential of guanosine.…”

Section: Other Pathwaysmentioning

confidence: 84%

In search of antiepileptogenic treatments for post-traumatic epilepsy

Saletti

Ali

Casillas‐Espinosa

et al. 2019

Neurobiology of Disease

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Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.

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Section: Other Pathwaysmentioning

confidence: 84%

In search of antiepileptogenic treatments for post-traumatic epilepsy

Saletti

Ali

Casillas‐Espinosa

et al. 2019

Neurobiology of Disease

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“…The decreased gene and protein expressions of SUCLG1 and the overall inhibition of the TCA cycle might indirectly contribute to the well-known phenomenon of glutamate excitotoxicity. This occurs under various states of brain distress, including TBI [18,48,49]. It is conceivable that a decreased rate of the TCA cycle after sTBI may produce an initial increase in the intracellular concentrations of TCA intermediates, particularly keto-acids and more specifically α-ketoglutarate.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement

Lazzarino

Amorini

Signoretti

et al. 2019

IJMS

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Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of mitochondrial tricarboxylic acid cycle (TCA). TBI was induced in anaesthetized rats by dropping 450 g from 1 (mTBI) or 2 m height (sTBI). After 6 h, 12 h, 24 h, 48 h, and 120 h gene expressions of enzymes and subunits of PDH. PDH kinases and phosphatases (PDK1-4 and PDP1-2, respectively), citrate synthase (CS), isocitrate dehydrogenase (IDH), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase (SDH), succinyl-CoA synthase (SUCLG), and malate dehydrogenase (MDH) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). In the same samples, the high performance liquid chromatographic (HPLC) determination of acetyl-coenzyme A (acetyl-CoA) and free coenzyme A (CoA-SH) was performed. Sham-operated animals (n = 6) were used as controls. After mTBI, the results indicated a general transient decrease, followed by significant increases, in PDH and TCA gene expressions. Conversely, permanent PDH and TCA downregulation occurred following sTBI. The inhibitory conditions of PDH (caused by PDP1-2 downregulations and PDK1-4 overexpression) and SDH appeared to operate only after sTBI. This produced almost no change in acetyl-CoA and free CoA-SH following mTBI and a remarkable depletion of both compounds after sTBI. These results again demonstrated temporary or steady mitochondrial malfunctioning, causing minimal or profound modifications to energy-related metabolites, following mTBI or sTBI, respectively. Additionally, PDH and SDH appeared to be highly sensitive to traumatic insults and are deeply involved in mitochondrial-related energy metabolism imbalance.

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“…Traumatic brain injury (TBI), one of the major health problems worldwide, is estimated to affect over 10 million people annually [1]. There are two forms of brain injury in TBI: primary injuries which cannot be interrupted once happened and secondary injuries which result in a cascade of cellular and molecular responses that aggravate the primary injuries [2].…”

Section: Introductionmentioning

confidence: 99%

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

Gao

Huang

et al. 2016

Mol Neurobiol

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Excessive inflammation after traumatic brain injury (TBI) is a major cause of secondary TBI. Though several inflammatory biomarkers have been postulated as the risk factors of TBI, there has not been any comprehensive description of them. Fingolimod, a new kind of immunomodulatory agent which can diminish various kinds of inflammatory responses, has shown additional therapeutic effects in the treatment of intracranial cerebral hematoma (ICH), ischemia, spinal cord injury (SCI), and many other CNS disorders. However, its therapeutic application has not been confirmed in TBI. Thus, we hypothesized that a 3-day consecutive fingolimod administration could broadly modulate the inflammatory reactions and improve the outcomes of TBI. The TBI models of C57/BL6 mice were established with the controlled cortical impact injury (CCI) system. A 3-day consecutive fingolimod therapy (given at 1, 24, and 48 h post injury) was performed at a dose of 1 mg/kg. The flow cytometry, immunoflourence, cytokine array, and ELISA were all applied to evaluate the immune cells and inflammatory markers in the injured brains. Immunohistochemical staining with anti-APP antibody was performed to assess the axonal damage. The neurological functions of these TBI models were assessed by mNSS/Rota-rod and Morris water maze (MWM). The brain water content and integrity of the blood-brain barrier (BBB) were also observed. On the 3rd day after TBI, the accumulation of inflammatory cytokines and chemokines reached the peak and administration of fingolimod reduced as many as 20 kinds of cytokines and chemokines. Fingolimod decreased infiltrated T lymphocytes and NK cells but increased the percentage of regulatory T (Treg) cells, and the concentration of IL-10 on the 3rd day after TBI. Fingolimod also notably attenuated the general activated microglia but augmented the M2/M1 ratio accompanied by decreased axonal damage. The neurological functions were improved after the fingolimod treatment accompanied with alleviation of the brain edema and BBB damage. This study suggests that the 3-day consecutive fingolimod administration extensively modulates multiple immuno-inflammatory responses and improves the neurological deficits after TBI, and therefore, it may be a new approach to the treatment of secondary TBI.

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Guanosine Protects Against Traumatic Brain Injury-Induced Functional Impairments and Neuronal Loss by Modulating Excitotoxicity, Mitochondrial Dysfunction, and Inflammation

Cited by 38 publications

References 62 publications

In search of antiepileptogenic treatments for post-traumatic epilepsy

In search of antiepileptogenic treatments for post-traumatic epilepsy

Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

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