Biology subjects

Pischiutta, F.

Publications and source records attributed to Pischiutta, F..

3 recordsLinked to original sources

bioRxiv2025

Brain infiltrating T cells mediate microglial dysregulation and neuronal loss following SAH

The contribution of T cells to neuroinflammation after aneurysmal subarachnoid hemorrhage (SAH) remains poorly understood. Using a murine pre-chiasmatic injection model of SAH we demonstrate that T cell infiltration into the brain modulates microglial activation and promotes neuronal death. Targeted transcriptomic profiling revealed a sustained neuroimmune response at 7 days post injury (dpi) characterized by a major involvement of T cells and microglia activation. Immunohistochemistry confirmed focal CD3+ T cell infiltration, predominantly CD4+, in the brain at the site of blood injection (BI), choroid plexus and meninges in SAH mice at 3- and 7-dpi. This temporal pattern was also observed in the CSF of a human SAH cohort. T cell presence spatially correlated with regions of microglial reactivity and neuronal loss. Notably, CD3-knockout mice exhibited reduced microglial activation and preserved neuronal viability. These findings identify T cells as key amplifiers of post-SAH neuroinflammation and neuronal damage. Targeting T cell-microglia crosstalk may represent a novel therapeutic avenue for SAH. Summary statementThis study shows that brain T-cell infiltration after subarachnoid hemorrhage drives microglial activation and neuronal loss in mice, with similar patterns observed in patients. Data indicate T cells as key mediators of post-injury neuroinflammation with therapeutic implications.

neuroscience↗

bioRxiv2023

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing potential new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%, perhaps due, in part, to distinct timescales of pathophysiological processes in rodents versus humans that impedes translational advancements. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to human TBI biomechanics and pathophysiology. To support this important translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used NfL, t-Tau, p-Tau, UCH-L1, or GFAP, published in PubMed/MEDLINE up to June 13th, 2023. We focused on blood biomarker temporal trajectories and their predictive and pharmacodynamic value and discuss our findings in the context of the latest clinical TBI biomarker data. Out of 369 original studies identified through the literature search, 71 met the inclusion criteria, with a median quality score on the CAMARADES checklist of 5 (interquartile range 4-7). NfL was measured in 17 preclinical studies, GFAP in 41, t-Tau in 17, p-Tau in 7, and UCH-L1 in 19 preclinical studies. Data in rodent models show that all blood biomarkers exhibited injury severity-dependent elevations, with GFAP and UCH-L1 peaking within hours after TBI, NfL peaking within days after TBI and remaining elevated up to 6 months post-injury, whereas t-Tau and p-Tau levels were gradually increased many weeks after TBI. Blood NfL levels emerges as a prognostic indicator of white matter loss after TBI, while both NfL and GFAP hold promise for pharmacodynamic studies of neuroprotective treatments. Therefore, blood-based preclinical biomarker trajectories could serve as important anchor points that may advance translational research in the TBI field. However, further investigation into biomarker levels in the subacute and chronic phases will be needed to more clearly define pathophysiological mechanisms and identify new therapeutic targets for TBI.

neuroscience↗

bioRxiv2023

Hypertonic lactate infusion reduces vasopressor requirement and biomarkers of brain and cardiac injury after experimental cardiac arrest

IntroductionPrognosis after resuscitated cardiac arrest (CA) remains poor with high morbidity and mortality due to extensive cardiac and brain injuries and the lack of effective treatments. Hypertonic sodium lactate (HSL) could be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as alternative energetic cellular substrate. The aim of this study was therefore to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA. MethodsAfter a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine (n=35) were randomly assigned to receive either balanced crystalloids (controls, n=11) or HSL infusion, either starting during cardiopulmonary resuscitation (CPR, Intra-arrest, n=12) or after return of spontaneous circulation (Post-ROSC, n=11) for the following 12 hours. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with target temperature management at 34{degrees}C. Results34 out of 35 (97.1%) animals achieved ROSC and one animal in the Intra-arrest group deceased before completing the observation period. Arterial pH, lactate, sodium concentrations and plasma osmolarity were higher in treated animals then in controls (p<0.001), while potassium concentrations were lower (p=0.004). HSL infusion either Intra-arrest or Post-ROSC improved hemodynamic compared to controls, as shown by reduced vasopressors need to maintain mean arterial pressure target above 65 mmHg (p=0.005 for interaction; p=0.01 for groups). Moreover, plasmatic troponin-I levels and glial fibrillary acid protein (GFAP) concentrations were lower in treated groups at several time-points than in controls. ConclusionsIn this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasmatic levels of biomarkers of cardiac and cerebral injury.

neuroscience↗