Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Screening out irrelevant cell-based models of disease

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell-and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates

Analyzing subcomponents of affective dysregulation in borderline personality disorder in comparison to other clinical groups using multiple e-diary datasets

Background: Affective dysregulation is widely regarded as being the core problem in patients with borderline personality disorder (BPD). Moreover, BPD is the disorder mainly associated with affective dysregulation. However, the empirical confirmation of the specificity of affective dysregulation for BPD is still pending. We used a validated approach from basic affective science that allows for simultaneously analyzing three interdependent components of affective dysregulation that are disturbed in patients with BPD: homebase, variability, and attractor strength (return to baseline). Methods: We applied two types of multilevel models on two e-diary datasets to investigate group differences regarding three subcomponents between BPD patients (n =43; n =51) and patients with posttraumatic stress disorder (PTSD; n= 28) and those with bulimia nervosa (BN; n= 20) as clinical control groups in dataset 1, and patients with panic disorder (PD; n= 26) and those with major depression (MD; n =25) as clinical control groups in dataset 2. In addition, healthy controls (n= 28; n= 40) were included in the analyses. In both studies, e-diaries were used to repeatedly collect data about affective experiences during participants’ daily lives. In study 1 a high-frequency sampling strategy with assessments in 15 min-intervals over 24 h was applied, whereas the assessments occurred every waking hour over 48 h in study 2. The local ethics committees approved both studies, and all participants provided written informed consent. Results: In contradiction to our hypotheses, BPD patients did not consistently show altered affective dysregulation compared to the clinical patient groups. The only differences in affective dynamics in BPD patients emerged with regard to one of three subcomponents, affective homebase. However, these results were not even consistent. Conversely, comparing the patients to healthy controls revealed a pattern of more negative affective homebases, higher levels of affective variability, and (partially) reduced returns to baseline in the patient groups. Conclusions: Our results indicate that affective dysregulation constitutes a transdiagnostic mechanism that manifests in similar ways in several different mental disorders. We point out promising prospects that might help to elucidate the common and distinctive mechanisms that underlie several different disorders and that should be addressed in future studies