Antibody-mediated inhibition of tissue-type plasminogen activator binding to the low-density lipoprotein receptor-related protein 1 as a potential beneficial modulator for stroke therapy.

The acute ischemic stroke therapy of choice is the application of Alteplase, a drug containing the enzyme tissue-type plasminogen activator (tPa) which rapidly destabilizes blood clots. A central hallmark of stroke pathology is blood-brain barrier (BBB) breakdown associated with tight junction (TJ) protein degradation, which seems to be significantly more severe under therapeutic conditions. The exact mechanisms how tPa facilitates BBB breakdown are not entirely understood. There is evidence that an interaction with the lipoprotein receptor-related protein 1 (LRP1), allowing tPa transport across the BBB into the central nervous system, is necessary for this therapeutic side effect. Whether tPa-mediated disruption of BBB integrity is initiated directly on microvascular endothelial cells or other brain cell types is still elusive. In this study we could not observe any changes of barrier properties in microvascular endothelial cells after tPa incubation. However, we present evidence that tPa causes changes in microglial activation and BBB breakdown after LRP1-mediated transport across the BBB. Using a monoclonal antibody targeting the tPa binding sites of LRP1 decreased tPa transport across an endothelial barrier. Our results indicate that limiting tPa transport from the vascular system into the brain by coapplication of a LRP1-blocking monoclonal antibody might be a novel approach to minimize tPa-related BBB damage during acute stroke therapy.

Luteolin in the Qi Bi Anshen decoction improves propionic acid-induced autism-like behavior in rats by inhibiting LRP1/MMP9.

BACKGROUND: A neurodevelopmental illness with a high frequency and unidentified pathophysiology is known as autism spectrum disorder (ASD). A research hotspot in this field is the identification of disease-specific biomarkers and drug intervention targets. Traditional Chinese medicine (TCM) can eliminate the symptoms of autism by precisely regulating human physiology. The Qi Bi Anshen decoction (QAT) is a commonly used TCM clinical drug commonly-used to treat for treating ASD. However, the primary active ingredients and underlying mechanisms of action of this decoction remain unknown. PURPOSE: This study aimed to investigate the active ingredients and pharmacodynamics of QAT in the treatment of ASD using a Sprague-Dawley rat model that resembled autism. METHODS: Autism-like rat models were established through intracerebroventricular injections of propionic acid (PPA). Subsequently, the rats were treated with QAT, and their efficacy was evaluated using the three-chamber method to analyze social interactions and grooming behavior. Additionally, open-field tests, elevated cross-maze tests, hematoxylin and eosin staining, Nissl staining, and enzyme-linked immunosorbent assays were performed; Western blot analysis was employed to determine the expression of synaptic plasticity-related proteins. Utilizing ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS), the effectiveness of active QAT components was assessed, and potential QAT targets were screened through molecular docking, surface plasmon resonance, and thermal migration experiments. To better understand the precise processes involved in treating ASD with active QAT components, in vivo and in vitro knockdown tests were also performed. RESULTS: QATexhibited a significant improvement in autism-like behavior and a notable increase in the production of proteins associated with synaptic plasticity. Furthermore, luteolin (LUT), identified as a potentially important active ingredient in QAT for treating ASD, reduced matrix metallopeptidase-9 (MMP9) expression. However, this effect was attenuated by the knockdown of low-density lipoprotein receptor-associated protein 1 (LRP1), which is the target binding site for LUT. CONCLUSIONS: LUT emerges as a potentially crucial active component of QAT in the treatment of ASD, with the ability to antagonize LRP1 and subsequently reduce MMP9 expression.

A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents.

Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact alpha-chain (sLRP-alpha), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-alpha into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-alpha and IL-1beta locally. sLRP-alpha also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-alpha inhibited TNF-alpha-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-alpha did not involve TNF-alpha binding, but rather glial cell preconditioning, so that the subsequent response to TNF-alpha was inhibited. Our results show that sLRP-alpha is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.

Frontal variant of Alzheimer's disease and typical Alzheimer's disease: A comparative study / La variante frontal de la enfermedad de Alzheimer y la enfermedad de Alzheimer típica: un estudio comparativo

Una de las características de la Enfermedad de Alzheimer (EA) es su heterogeneidad clínica. Así, la presentación atípica frontal o disejecutiva es cada vez más conocida, aunque los factores subyacentes se desconocen. En este estudio se comparó el rendimiento neuropsicológico de dos grupos de pacientes con EA (variante frontal -EAvf- y típica -EAT-). El grupo EAvf (n = 13) fue seleccionado por la existencia de una hipocaptación frontal. Los resultados revelaron que el grupo EAvf manifestó un tras-torno disejecutivo grave, una sintomatología neuropsiquiátrica más severa (desinhibición y apatía), mayor deterioro funcional y generó mayor sobre-carga en el cuidador que el grupo EAT sin afectación frontal (n = 47). A pesar de que el grupo EAvf rindió más bajo en todos los test neuropsicológicos, solo se encontraron diferencias significativas entre ambos grupos en las tareas de velocidad de procesamiento y visuoconstrucción. El análisis de regresión logística reveló que las puntuaciones de velocidad de procesa-miento y flexibilidad mental predicen significativamente el diagnostico de EAvf. La existencia de reflejo de graspin, anosognosia y la no posesión del APOE e4 también fue más prevalente en el grupo EAvf. Este grupo mostró una predominancia de varones y fue más propenso a tener una historia familiar positiva para la EA. Para concluir, el estudio sugiere que la EAvf representa un subtipo de EA que parece tener características clínicas, neuropsicológicas y genéticas diferentes a la EAT (AU)

Clinical heterogeneity is one of the characteristics of Alzheimer's disease (AD). Hence, the atypical frontal or dysexecutive presentation is becoming increasingly well-known, although the underlying factors are still unknown. In this study, the neuropsychological performance of two groups of patients with AD (frontal variant-ADfv-and typical-TAD) were compared. The ADfv group (n = 13) was selected due to the existence of frontal hypoperfusion on a simple photon emission computer tomography (SPECT). The results revealed that the ADfv group displayed a severe dysexecutive disorder, more severe neuropsychiatric symptomatology (disinhibition and apathy), more functional impairment, and it generated a higher caregiver overload than the TAD group without frontal impairment (n = 47). Despite the facts that the ADfv group’s performance was poorer in all the neuropsychological tests, significant group differences were only found in the processing speed and visuoconstruction tasks. Lo-gistic regression analysis revealed that the processing speed and mental flexibility scores significantly predicted a diagnosis of ADfv. The existence of the grasp reflex, anosognosia, and the absence of apolipoprotein E epsilon 4 allele (APOE e4) were also more prevalent in the ADfv group. This group had a predominance of males and it was more likely to have a positive family history of AD. To conclude, the study suggests that ADfv represents a subtype of AD that seems to have different clinical, neuropsychological, and genetic characteristics from TAD (AU)

Inhibidores de PCSK-9, efectos sobre el cLDL e implicaciones futuras: lo que se debe saber / PCSK-9 inhibitors, effects on LDL-C and future implications: What you should know

El descubrimiento de la proproteína convertasa de subtilisina/kexina tipo 9 (PCSK9) en el año 2003 en familias con hipercolesterolemia familiar (HF) generó posteriormente el desarrollo de estrategias farmacológicas a fin de inhibir esta proteína. Doce años después de este descubrimiento, se logró la aprobación de los 2 primeros compuestos biológicos (anticuerpos monoclonales) que han demostrado disminuir en forma sustancial el cLDL y otras subfracciones lipídicas. El objetivo del presente artículo es repasar la historia del descubrimiento de la PCSK9, de su fisiología y fisiopatología, y del posterior desarrollo farmacológico. Se plantean los objetivos y las metas alcanzados a la fecha y las cuestiones pendientes en cuanto a la eficacia y la seguridad de su uso clínico

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions. The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented