In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury—Lessons Learned

Lipponen, Anssi; Natunen, Teemu; Hujo, Mika; Ciszek, Robert; Hämäläinen, Elina; Tohka, Jussi; Hiltunen, Mikko; Paananen, Jussi; Poulsen, David J.; Kansanen, Emilia; Ndode-Ekane, Xavier Ekolle; Levonen, Anna–Liisa; Pitkänen, Asla

doi:10.3390/ijms20215395

Cited by 9 publications

(11 citation statements)

References 104 publications

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“…Even with the strong in vitro efficacy of a drug, the in vivo validation process may not be sensitive enough to demonstrate favorable in vivo effects [ 72 ]. As our in vitro study indicated, not only monotherapy with SFN but also monotherapy with NAC had anti-inflammatory potential.…”

Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury

Kyyriäinen

Kajevu

Bañuelos

et al. 2021

IJMS

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We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N-acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% (p < 0.001) and neuroinflammation to –29% (p < 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control (p < 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls (p < 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.

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Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury

Kyyriäinen

Kajevu

Bañuelos

et al. 2021

IJMS

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“…The cerebral cortex of each of the E18 embryos was dissected and the neuronal cells were plated as described earlier [ 41 , 42 ]. Briefly, the cortex was dissected under a stereomicroscope in Dulbecco’s modified Eagles medium (DMEM; #BE12-614F, Lonza, Basel, Switzerland), supplemented with 10% fetal bovine serum (#10270-106, Thermo Fisher Scientific, Waltham, MA, USA) and 2 mM l-glutamine (#BE17-605E, Lonza).…”

Section: Methodsmentioning

confidence: 99%

Gene Expression Profile as a Predictor of Seizure Liability

Lipponen

Kajevu

Natunen

et al. 2023

IJMS

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Analysis platforms to predict drug-induced seizure liability at an early phase of drug development would improve safety and reduce attrition and the high cost of drug development. We hypothesized that a drug-induced in vitro transcriptomics signature predicts its ictogenicity. We exposed rat cortical neuronal cultures to non-toxic concentrations of 34 compounds for 24 h; 11 were known to be ictogenic (tool compounds), 13 were associated with a high number of seizure-related adverse event reports in the clinical FDA Adverse Event Reporting System (FAERS) database and systematic literature search (FAERS-positive compounds), and 10 were known to be non-ictogenic (FAERS-negative compounds). The drug-induced gene expression profile was assessed from RNA-sequencing data. Transcriptomics profiles induced by the tool, FAERS-positive and FAERS-negative compounds, were compared using bioinformatics and machine learning. Of the 13 FAERS-positive compounds, 11 induced significant differential gene expression; 10 of the 11 showed an overall high similarity to the profile of at least one tool compound, correctly predicting the ictogenicity. Alikeness-% based on the number of the same differentially expressed genes correctly categorized 85%, the Gene Set Enrichment Analysis score correctly categorized 73%, and the machine-learning approach correctly categorized 91% of the FAERS-positive compounds with reported seizure liability currently in clinical use. Our data suggest that the drug-induced gene expression profile could be used as a predictive biomarker for seizure liability.

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“…developed a unique pipeline for TBI treatment discovery using transcriptomics data. [ 43 ] The outcomes of their approach identified several potential drug candidates that could modulate the inflammatory response post-TBI, offering a new avenue for TBI treatment. [ 43 ]…”

Section: Targeting Inflammation and Oxidative Stressmentioning

confidence: 99%

Neuroprotection strategies in traumatic brain injury: Studying the effectiveness of different clinical approaches

Buccilli,

Alan,

Baha’

et al. 2024

Surgical Neurology International

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Background: This review delves into clinical strategies aimed at addressing the complexities of traumatic brain injury (TBI), specifically focusing on pharmaceutical interventions and stem cell therapies as potential avenues for enhancing TBI outcomes. Methods: A thorough review of clinical strategies for TBI management, encompassing pharmaceutical and nonpharmaceutical interventions, was performed. PubMed, MEDLINE and clinical trial databases were searched to identify relevant studies and clinical trials. Inclusion criteria consisted of studies involving pharmaceutical agents and other clinical approaches (i.e., stem cell therapies) targeting neuroinflammation, excitotoxicity, oxidative stress, and neurodegeneration in TBI. Data from clinical trials and ongoing research initiatives were analyzed to assess the current status and potential of these clinical approaches. Results: Many trials have been conducted to face the challenge that is TBI. These interventions are designed to target critical aspects of secondary brain injury, encompassing neuroinflammation, excitotoxicity, oxidative stress, and neurodegeneration. Despite this, there is no panacea or definitive remedy for this condition. Combining therapies in a patient-tailored approach seems to be our best chance to improve these patients’ outcomes, but systematic protocols are needed. Conclusion: Clinical strategies represent dynamic and continually evolving pathways in TBI management. This review provides an extensive overview of the existing landscape of clinical approaches and promising new studies and outlines their influence on patient outcomes. By highlighting challenges and presenting opportunities, it contributes to the ongoing mission to advance clinical care for individuals impacted by TBI.

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In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury—Lessons Learned

Cited by 9 publications

References 104 publications

Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury

Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury

Gene Expression Profile as a Predictor of Seizure Liability

Neuroprotection strategies in traumatic brain injury: Studying the effectiveness of different clinical approaches

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