Abstract
Several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules in the brain of 14-day-old (PND14) Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the protein levels of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors tropomyosin-related kinase (TrkA and TrkB) and downstream kinases Akt and the extracellular signal regulated kinase (ERK) were assessed by Western immunoblot analysis at different time points during the first 24 h after the treatment, as well as the expression of cleaved caspase-3 fragment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons. The obtained results show that the treatment caused marked alterations in levels of the examined neurotrophins, their receptors and downstream effector kinases. However, these changes were not associated with increased neurodegeneration in either the cortex or the thalamus. These results indicate that in the brain of PND14 rats, the interaction between Akt/ERK signaling might be one of important part of endogenous defense mechanisms, which the developing brain utilizes to protect itself from potential anesthesia-induced damage. Elucidation of the underlying molecular mechanisms will improve our understanding of the age-dependent component of anesthesia-induced neurotoxicity.
Highlights
General anesthetics are routinely used in the clinic and their safety is usually determined by the clinical outcome [1]
The binding of neurotrophins to Trk receptors induces their dimerization which is followed by autophosphorylation of tyrosine residues within the intracellular kinase domain, that leads to the activation of signaling pathways such as the phosphatidylinositol 3kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/ extracellular signal regulated kinase (ERK) pathways [5,8]
brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors (TrkB and TrkA, respectively) and downstream kinases (Akt and ERK) in the cortex and in the thalamus of postnatal day 14 (PND14) rats, two brain areas involved in the actions of anesthetics
Summary
General anesthetics are routinely used in the clinic and their safety is usually determined by the clinical outcome [1]. The neurotrophins are a family of secreted proteins that mediate numerous functions in both the developing and mature nervous system, including growth, survival, differentiation and synaptic plasticity of postmitotic neurons [5]. They are comprised of the NGF, BDNF, neurotrophin 3 (NT-3) and neurotrophin 4/5 (NT4/5) [6]. Akt and ERK kinases play a crucial role in regulating various processes in the brain, including neuronal proliferation, differentiation, development, migration, survival and long-term synaptic plasticity [9,10]. In our previous study [14], we reported that short-term propofol anesthesia could have a neurotoxic effect in the cortex and thalamus of PND7 rats and that this effect is mediated, at least in part, by neurotrophic downregulation
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