Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous PACAP therefore results in a variety of abnormalities. One of the important effects of PACAP is its neuroprotective and general cytoprotective role. PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from PACAP-deficient mice provide evidence that endogenous PACAP also has protective functions. Mice lacking PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of PACAP-deficient mice against harmful stimuli. Mice lacking PACAP respond with a higher degree of injury in cerebral ischemia, autoimmune encephalomyelitis, and axonal lesion. Retinal ischemic and excitotoxic injuries also produce increased cell loss in PACAP-deficient mice. In peripheral organs, kidney cell cultures from PACAP-deficient mice are more sensitive to oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient mice have a negative histological outcome and altered cytokine response in kidney and small intestine ischemia/reperfusion injury. Large intestinal inflammation, toxic lesion of the pancreas, and doxorubicin-induced cardiomyopathy are also more severe with a lack of endogenous PACAP. Finally, an increased inflammatory response has been described in subacute endotoxin-induced airway inflammation and in an oxazolone-induced allergic contact dermatitis model. In summary, lack of endogenous PACAP leads to higher vulnerability in a number of injuries in the nervous system and peripheral organs, supporting the hypothesis that PACAP is part of the endogenous cytoprotective machinery.
Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP immunoreactivity is co-localized with a neuronal marker, and PACAP receptor (PAC1-R) immunoreactivity is observed in mouse infraorbital lacrimal gland acinar cells. PACAP eye drops stimulate tear secretion and increase cAMP and phosphorylated (p)-protein kinase A levels in the infraorbital lacrimal glands that could be inhibited by pre-treatment with a PAC1-R antagonist or an adenylate cyclase inhibitor. Moreover, these eye drops suppress corneal keratinization in PACAP-null mice. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane and pAQP5 levels in the infraorbital lacrimal glands. AQP5 siRNA treatment of the infraorbital lacrimal gland attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder.
After central nervous system (CNS) injury, reactive astrocytes display opposing functions, inducing neural repair and axonal regeneration via the release of growth factors, or forming a glial scar which acts as a barrier to axonal regeneration. Endogenous neural stem/progenitor cells have also recently been identified at the site of CNS injury, where they have been shown to differentiate into mature neurons in an animal model of ischemia. However, the pathophysiological mechanisms underpinning the contribution of reactive astrocytes and neural stem/progenitor cells to neural repair are still to be fully elucidated. Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the CNS, where it has been shown to exert numerous biological effects. This review will summarize the current state of knowledge regarding the expression of PACAP and its receptors during neural development, as well as the involvement of PACAP in astrocytes and neural stem/progenitor cell biology. In addition, we will also discuss emerging evidence that implicates PACAP in neurogenesis and neural repair in response to brain pathophysiology.
BackgroundDirect laryngoscopy remains the gold standard for endotracheal intubation and is preferred by experienced operators. However, an increasing number of reports currently support videolaryngoscopy, particularly for novice users. The widespread use of videolaryngoscopy may be limited due to financial limitations, especially in low-income countries. Therefore, affordable single-use scopes are now becoming increasingly popular. We sought to compare these new scopes with direct laryngoscopes and the previously tested videolaryngoscopes in mannequins by novices.MethodsFifty medical students were recruited to serve as novice users. Following brief, standardized training, students were asked to execute endotracheal intubation with each of the devices, including the Airtraq®, a custom-made videolaryngoscope, the King Vision®, the Macintosh laryngoscope and the VividTrac®, on an airway trainer (Laerdal Airway Management Trainer®) in normal and difficult airway scenarios. We evaluated the time to and the proportion of successful intubation, the best view of the glottis, esophageal intubation, dental trauma and user satisfaction.ResultsWe observed no differences in esophageal intubation. However, intubation-related times, the view of the glottis and operator satisfaction were significantly better throughout the study with the commercial videolaryngoscopes. In comparison, the custom-made videolaryngoscope performance proved to be similar to that of the Macintosh laryngoscope. The VividTrac® performance was similar (P > 0.05) or significantly better than that of the King Vision® in both scenarios.ConclusionsBased upon our results, the Airtraq®, King Vision® and VividTrac® were superior to the Macintosh laryngscope in both normal and difficult airway scencarios for novice users. In particular, our study is the first to report that the VividTrac® shows promise for further clinical evaluation.
Although mood disorders are frequently genetically determined and to some degree gender-dependent, the concept of early life 'programming', implying a relation between perinatal environmental events and adult mood disorders, has recently gained considerable attention. In particular, maternal separation (MS) markedly affects various stress-sensitive brain centers. Therefore, MS is considered as a suitable experimental paradigm to study how early life events affect brain plasticity and, hence, cause psychopathologies like major depression. In adult mammals, the classical hypothalamo-pituitary-adrenal (HPA-) axis and the urocortin 1 (Ucn1)-containing non-preganglionic Edinger-Westphal nucleus (npEW) respond in opposite ways to chronic stressors. This raises the hypothesis that MS, which is known to increase vulnerability for adult mood disorders via the dysregulation of the HPA-axis, will affect npEW dynamics as well. We have tested this hypothesis and, moreover, studied a possible role of brain-derived neurotrophic factor (BDNF) in such npEW plasticity. By triple immunocytochemistry we show that BDNF and Ucn1 coexist in rat npEW-neurons that are c-Fos-positive upon acute stress. Quantitative immunocytochemistry revealed that MS increases the contents of Ucn1 and BDNF in these cells. Furthermore, in males and females, the c-Fos response of npEW-Ucn1 neurons upon restraint stress was blunted in animals with MS history, a phenomenon that was concomitant with dampening of the HPA corticosterone response in females but not in males. Based on these data we suggest that the BDNF-containing npEW-Ucn1 system might be affected by MS in a sex-specific manner. This supports the idea that the npEW would play a role in the appearance of sex differences in the pathogenesis of stress-induced mood disorders.
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