Biology subjects

Lopez-Rodriguez, A. B.

Publications and source records attributed to Lopez-Rodriguez, A. B..

4 recordsLinked to original sources

bioRxiv2022

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder.

Autism Spectrum Disorders (ASD) are predominantly developmental in nature and largely genetically determined. There are some human data supporting the idea that fever can improve symptoms in some individuals but the human data for this are limited and there are almost no data to support this from animal models. In the current study we used a whole body hyperthermia (WBH) protocol and systemic inflammation induced by bacterial endotoxin (LPS) to dissociate temperature and inflammatory elements of fever in order to examine the impact of these environmental stressors on behavioural signs in two animal models relevant to ASD: C58BL/6 and Shank3B- mice. While only LPS induced inflammatory signatures in the brain, WBH and LPS induced both overlapping and distinct neuronal cFos activation in several brain regions and modest effects on heat shock gene expression. In behavioural experiments LPS significantly suppressed most activities over 24-48 hours while WBH reduced repetitive behaviours and improved social interaction in C58BL/6 mice. In Shank3B- mice WBH significantly reduced compulsive grooming. The data are the first, to our knowledge, to demonstrate that elevated body temperature, in the absence of underpinning inflammation, can improve some behavioural signs in two distinct animal models of ASD. Given the developmental and genetic nature of ASD, evidence that symptoms may be ameliorated by environmental perturbations indicates that there are possibilities for improving function in these individuals.

neuroscience↗

bioRxiv2020

Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

Background and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1{beta} and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit. MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining. ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1{beta}, TNF-), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration. ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

neuroscience↗

bioRxiv2019

Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, that while adaptive for the organism, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here we used bacterial lipopolysaccharide (LPS) in C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 g/kg) induced hypoglycemia, which was mimicked by IL-1{beta} (25 g/kg) but not prevented in IL-1RI-/- mice, nor by IL-1RA (10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentration, was mitigated by exogenous glucose (2 g/kg) and was exacerbated by 2-deoxyglucose glycolytic inhibition, which prevented IL-1{beta} synthesis. Using the ME7 model of chronic neurodegeneration, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 g/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in cerebrospinal fluid (CSF) in humans during delirium, triggered by acute inflammatory trauma. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with altered brain energy metabolism. Collectively the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.

neuroscience↗

bioRxiv2018

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

Alzheimers disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by {beta}-amyloid pathology to induce exaggerated IL-1{beta} responses to acute stimulation with LPS or IL-1{beta}. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1{beta} induction nor NF{kappa}B p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1{beta}, NF{kappa}B-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1{beta} we demonstrate that astrocytes proximal to A{beta}-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1{beta}, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

neuroscience↗