Several antipsychotic drugs produce a neurotoxic mechanism resulting from an increased or decreased concentration of serotonin both in the synaptic and extracellular spaces. In this sense, drug exposure at 4 or 5 dpf coincides with the initial appearance of raphe axons distributed throughout the entire length of the spinal cord in zebrafish. Growth cones of these axons at 4 dpf were observed adjacent to reticulospinal neurons in the hindbrain and secondary motoneurons in the spinal cord.
The temporal correlation between the growth of inferior raphe axons and growth cones throughout the spinal cord and the earliest morphological effects of antipsychotic drugs suggested that raphe axons were affected by the exposure to these drugs. However, the mechanism of toxicity by excess or deficit of serotonin was difficult to determine. Antipsychotic drugs could alter extracellular levels of neurotransmitters and thereby modify the development of the CNS. These changes suggest that the neuroanatomy is severely affected by exposure to free Risp but to a lesser extent than by DG4.5-Risp. Chronic XL880 infection with hepatitis B virus affects 350 to 400 million individuals worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Although much is known about HBV structure and replicative cycle the pathogenic mechanisms responsible for liver injury, cirrhosis development and malignant transformation during chronic HBV infection are not well understood. It is believed that these events originate from persistent immune pathogenesis, but observations in transgenic mouse models of HBV infection suggest that in absence of an adaptive immune responses cellular mechanisms induced by HBV proteins may also lead to the development of these liver diseases.
The HBV transgenic mice used in the current study contain a sub-genomic HBV DNA fragment encoding the three co-carboxyterminal HBV surface proteins under the control of the liver-specific murine albumin promoter. Although these transgenic mice have been shown to develop chronic liver injury, regenerative hyperplasia, as well as adenomas and hepatocellular carcinomas the mechanisms of HBs proteins pathogenicity are poorly understood. The HBs protein expression pattern in this mouse model mimics the situation in the liver of patients with enhanced intracellular expression and retention of Hepatitis B virus surface proteins, e. g. patients with Hepatitis B virus-related chronic liver disease treated by transplantation. The liver damage in these patients was attributable to a direct hepatocytotoxic effect of HBV, since they were on a similar immunosuppresion regime.
Accumulation of misfolded proteins in the ER activates the unfolded protein response that is sensed by the binding immunoglobulin protein /glucose-regulated protein 78. Distinct branches of UPR are mediated by three different classes of ER-membrane transducers: inositolrequiring protein-1, activating transcription factor-6 or protein kinase-like endoplasmic reticulum kinase. PERK activation causes the phosphorylation of the alpha subunit of eukaryotic translation-initiation factor 2.