Search

Peripheral neuropathy is one of the major adverse effects that limit the clinical application of bortezomib (BTZ). However, the underlying mechanisms of BTZ-induced peripheral neuropathy (BIPN) remain elusive. To examine cell types potentially involved in the development of BIPN, we used four purified cultures of cells of the peripheral nervous system: Schwann cells (SCs), satellite glial cells (SGCs), macrophages, and dorsal root ganglion (DRG) neurons. Administration of a low BTZ concentration (5 nM; similar to concentrations in clinical use) caused dedifferentiation of cultured SCs, returning mature SCs to an immature state. In cultured SGCs, BTZ increased glial fibrillary acidic protein (GFAP) levels without inducing the release of inflammatory cytokines or chemokines. In macrophages, BTZ caused little inflammatory response. Finally, in DRG neurons, BTZ strongly suppressed the expression levels of sensor and transducer ion channels without affecting cell morphology. Taken together, low concentrations of BTZ can cause SC dedifferentiation (i.e., demyelination), increased GFAP level in SGC, and decreased expression levels of sensor and transducer ion channels in DRG neurons (i.e., numbness feeling). Thus, we have reported, for the first time, specific effects of BTZ on peripheral nervous system cells, thereby contributing to a better understanding of the initiating mechanism of BIPN.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms, including impairments in social behavior and repetitive interests. Recent studies have revealed that individuals with ASD also display decreased empathy, ultimately leading to difficulties in social relationships; however, another report indicated that individuals with ASD have enhanced emotional empathy. Nonetheless, the neurobiological mechanisms underlying altered empathy in individuals with ASD remain unclear. In this study, we assessed empathy-like behaviors in valproic acid (VPA)-treated mice-a mouse model of ASD with observational fear learning. We then investigated the brain regions and signaling systems responsible for the altered empathy-like behaviors in VPA-treated mice. As a result, mice prenatally exposed to VPA displayed increased empathy-like behaviors, which were not attributed to altered sensitivity to auditory stimuli or enhanced memory for pain-related contexts. Immunohistochemical analysis revealed that the number of c-Fos positive oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly higher in VPA-treated mice after observational fear learning. Finally, we found that pretreatment with L-368899, an antagonist of the oxytocin receptor, repressed the empathetic behavior in VPA-treated mice. These results suggest that VPA-treated ASD model animals showed increased emotional empathy-like behaviors through the hyperactivation of PVN oxytocinergic neurons for the first time. Further investigation of this hyperactivity will help to identify extrinsic stimuli and the condition which are capable of activation of PVN oxytocinergic neurons and to identify novel approach to enhance oxytocin signaling, which ultimately pave the way to development of novel therapy for ASD.

Central nervous system (CNS) inflammation is a potential therapeutic target for neurodegenerative diseases. In recent years, a number of studies have focused on the links between neurodegenerative diseases and CNS glial cells, especially microglia. Microglia are the main resident immune cells in the CNS and represent approximately 10-15% of all CNS cells. Microglia play an important role in maintaining brain homeostasis at rest by surveying the environment, and engulfing apoptotic cells and debris in the healthy brain. However, under certain pathological conditions, microglia can generate neurotoxic factors, such as pro-inflammatory cytokines and molecules like nitric oxide (NO), which lead to CNS inflammatory diseases. In this review, we discuss the evidence that regulation of microglial ion channels may modulate CNS inflammation and subsequent tissue damage in neurological disorders. In particular, we discuss the role of transient receptor potential (TRP) channels in microglia in both acute and chronic inflammatory conditions, and describe the physiological and pathophysiological roles of TRP channels in CNS inflammatory pathways. Additionally, we describe the benefits of stimulation/inhibition of TRP channels in animal models of microglia-related CNS inflammatory diseases.

Astrocytes, the most abundant cells in the central nervous system (CNS), play diverse roles in the regulation of neuronal activity, vascular function and gliotransmitter release. In neurodegenerative diseases, pathologically activated astrocytes show astrogliosis, which is clinically characterized by an abnormal cell morphology and excessive astrocyte proliferation. Thrombin, a crucial factor for brain injury after intracerebral hemorrhage, activates astrocytic Ca2+ signaling through a specific subtype of the thrombin receptor, termed the proteinase-activated receptor (PAR). In this study, we demonstrate a novel pathophysiological role for transient receptor potential canonical 3 (TRPC3) Ca2+-permeable nonselective cation channels in thrombin-activated astrocytes. In 1321N1 human astrocytoma cells and cultured rat cortical astrocytes, thrombin induced heterogeneous Ca2+ responses with asynchronous repetitive peaks. These oscillations were found to be the result of repetitive Ca2+ release from intracellular stores followed by replenishment of the stores with Ca2+ from the extracellular region. The oscillations occurred without a direct [Ca2+]i increase and were inhibited by the selective TRPC3 inhibitor pyrazole-3. Pharmacological manipulation with BAPTA-AM, cyclopiazonic acid, 2-aminoethoxydiphenyl borate and pyrazole-3 indicated that Ca2+ mobilization through TRPC3 was involved in thrombin-induced changes in the morphology of astrocytes. Moreover, thrombin-induced upregulation of S100B, a marker of reactive astrocytes, at 20 h and increased astrocytic proliferation at 72 h were inhibited by Ca2+ signaling blockers and knockdown of TRPC3 with specific siRNA. Taken together, these results suggest that TRPC3 may constitute a new therapeutic target for brain injury after intracerebral hemorrhage.