JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression

Furtado, Andrezza Bond Vieira; Gonçalves, Débora Farina; Hartmann, Diane Duarte; Courtes, Aline Alves; Cassol, Gustavo; Nuñez-Figueredo, Yanier; Argolo, Deivison Silva; Nascimento, Ravena Pereira do; Costa, Sílvia Lima; Silva, Víctor Diógenes Amaral da; Royes, Luiz Fernando Freire; Soares, Félix Alexandre Antunes

doi:10.1007/s12035-021-02436-4

Cited by 9 publications

(3 citation statements)

References 93 publications

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“…2 A). These shifts are consistent with reports of neuronal loss ( Bu et al 2016 ; Holden et al 2021 ; Jamjoom et al 2021 ) and glial responses postinjury, such as neuroinflammatory responses induced by microglia and demyelination related to oligodendrocyte pathology ( Chiu et al 2016 ; Furtado et al 2021 ; Matson et al 2022 ). Notably, clusters 13 and 15, two neuron subtypes, were only observed in the mTBI group ( Fig.…”

Section: Resultssupporting

confidence: 91%

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury

Yang,

Zhang,

et al. 2023

Genome Res.

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The subventricular zone (SVZ) is a neurogenic niche that contributes to homeostasis and repair after brain injury. However, the effects of mild traumatic brain injury (mTBI) on the divergence of the regulatory DNA landscape within the SVZ and its link to functional alterations remain unexplored. In this study, we meticulously mapped the transcriptome atlas of murine SVZ and its responses to mTBI at the single-cell level. We observed cell-specific gene expression changes following mTBI and unveiled diverse cell-to-cell interaction networks that influence a wide array of cellular processes. Moreover, we reported novel neurogenesis lineage trajectories and related key transcription factors, which we subsequently validated through loss-of-function experiments. Specifically, we validated the role ofTcf7l1, a cell cycle gene regulator, in promoting neural stem cell differentiation towards the neuronal lineage after mTBI, providing a potential target for regenerative medicine. Overall, our study profiles an SVZ transcriptome reference map, which underlies the differential cellular behavior in response to mTBI. The identified key genes and pathways that may ameliorate brain damage or facilitate neural repair serve as valuable resources for drug discovery in the context of mTBI.

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Section: Resultssupporting

confidence: 91%

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury

Yang,

Zhang,

et al. 2023

Genome Res.

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“…Recent research underscores the therapeutic potential of modulating the infiltration of peripheral cells and the activation of glial cells, particularly microglia and astrocytes, in TBI. Treatments that reduce the levels of pro-inflammatory molecular biomarkers, GFAP and the ionized calcium-binding adaptor molecule 1 (Iba1), have been associated with a lower inflammatory response, leading to the mitigation of injury-related deficits [61,62].…”

Section: Anti-inflammatory Agents and Immunomodulators In Traumatic B...mentioning

confidence: 99%

Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets

Silvestro,

Raffaele,

Quartarone

et al. 2024

IJMS

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A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI’s impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment.

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“…Different in vitro and in vivo preclinical models were performed [2][3][4] and multitarget mechanisms were demonstrated, including: (I) antioxidant and protective activities in brain-isolated mitochondria; (II) modulation of the glutamatergic system with no amnesic or addictive effects; (III) protective action against a non-physiological increase in intracellular calcium concentrations and (IV) anti-inflammatory and anti-apoptotic effects [2][3][4][5][6][7][8][9] . In addition to the neuroprotective properties described above, its protective potential has been demonstrated in models of dementia/cognitive deficit 10,11 and traumatic brain injury 12 . All these common mechanisms, which are seen in most common neurodegenerative diseases, led us to assume that it could be effective in the treatment of PD.…”

Section: Introductionmentioning

confidence: 99%

JM-20 administration to animals with lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine, partially reverses motor damage and oxidative stress

Fonseca-Fonseca,

Taño Portuondo,

Ramírez-Sánchez

et al. 2024

Preprint

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Previous studies have shown that JM-20, a new chemical hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. Also, we demonstrated that JM-20 blocks the formation of toxic alpha-synuclein aggregated species and aminochrome cytotoxicity. The present study sought to determine the neuroprotective property of JM-20 in animals with a partial lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine (6-OHDA). Forin vivostudies, adult male Wistar rats were lesioned in the rightsubstantia nigra pars compacta(SNpc) with 6-OHDA administration. Fifteen days after surgery, the animals asymmetry levels were assessed. Those with asymmetry values higher than 50% were divided into two groups: animals that did not receive any treatment and those that were administered with JM-20 (40 mg/kg, intragastric via gavage) for 27 days. Every seven days, the asymmetry values of the animals were analyzed until day 42 after the surgery. At the end of the experiment, the animals were euthanized and the SNpc and striatum were taken out for the analysis of oxidative stress. Our results reveal a behavioral function progressively recovered in the JM-20-treated animals, diminishing the percentage of motor asymmetry. Also, it improves some oxidative stress markers in the SNpc and the striatum of these animals. Our study provides the preclinical evidence to support the long-term neuroprotective potential of JM-20 in 6-OHDA hemiparkinson rat model, pointing out to its possible use as a disease-modifying agent in PD.

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JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression

Cited by 9 publications

References 93 publications

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury

Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets

JM-20 administration to animals with lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine, partially reverses motor damage and oxidative stress

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