Biology subjects

Laskowitz, D. T.

Publications and source records attributed to Laskowitz, D. T..

3 recordsLinked to original sources

bioRxiv2026

Recombinant GDF11 Improves Neurological Recovery in Models of Hemorrhagic Stroke and Traumatic Brain Injury

BackgroundIntracerebral hemorrhage (ICH) and traumatic brain injury (TBI) are leading causes of long-term neurological disability and mortality worldwide, with no approved therapies that promote functional recovery. Growth differentiation factor 11 (GDF11), a circulating TGF{beta}-family protein, has shown regenerative and neurorestorative potential in models of ischemic stroke. MethodsWe evaluated recombinant GDF11 (rGDF11) in mouse models of ICH and TBI. ICH was induced by intrastriatal collagenase injection, and neurological recovery was assessed using Neuroseverity Score (NSS), Rotarod (RR), and CatWalk (CW) analyses up to 28 days post-injury. Histological assessments of vascularization, neuronal density, and microglial/macrophage density were performed 28 days after ICH. For TBI, a closed-head injury model using a pneumatic impactor was employed, and NSS and RR assessments were conducted through 28 days post-injury. ResultsrGDF11 treatment significantly improved neurobehavioral performance following ICH, including NSS, RR, and CW parameters (forelimb base of support and average speed). Histological analyses revealed enhanced vascular area and neuronal density, with reduced microglial/macrophage density in rGDF11-treated mice. Following TBI, rGDF11 accelerated functional recovery, improving RR latency by day 6 and NSS by day 28 post-injury. ConclusionrGDF11 promotes structural and functional recovery after both hemorrhagic and traumatic brain injury in mice. These findings, together with prior evidence in ischemic stroke, support rGDF11 as a promising neurorestorative biologic with broad therapeutic potential for diverse forms of brain injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/730114v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@8c624forg.highwire.dtl.DTLVardef@8a6107org.highwire.dtl.DTLVardef@e83ce6org.highwire.dtl.DTLVardef@f65f14_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Optimization of a Translational Murine Model of Closed-head Traumatic Brain Injury

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability with limited effective interventions. Many TBI models impact brain parenchyma directly following craniotomy, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to an intact skull may lead to variability and as a result, modeling TBI remains a challenge. Moreover, current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on vestibulomotor performance, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing pressure beyond 70psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Females performed worse than males when injured at 2.7mm displacement, and had greater mortality at higher displacements. Stratifying severity based on day-1 rotarod performance retained cellular injury relationships and separated both sexes into injury severity cohorts with distinct behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.

neuroscience↗

bioRxiv2020

Neuroprotective pentapeptide, CN-105, improves outcomes in translational models of intracerebral hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age. MethodsIn three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2J mice, spontaneously hypertensive female rats, or 11-month old male mice within 24-hours of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively. ResultsIn spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91 - 153.70 and p < 0.001; 95% CI: 49.54 - 205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27 - 11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: -0.037 - -0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; {eta}2 = 0.093) and neuroseverity scores (p < 0.05; {eta}2 = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: -1.41 - -0.39). In 11-month old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; {eta}2 = 0.111) but not neuroseverity scores (p > 0.05; {eta}2 = 0.034). ConclusionsAcute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.

neuroscience↗