The neurogenic effects of exogenous neuropeptide Y: early molecular events and long-lasting effects in the hippocampus of trimethyltin-treated rats.

Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 \ub5g/2 \ub5l, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit

Continuity Under a Different Name: The Outcome of Privatisation in Serbia

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Normally, privatisation is seen as beneficial. This paper considers the case of Serbia–a latecomer in the matter–where privatisation was partly a result of exogenous pressures and where the process has been deemed a failure. In Serbia, a sizeable number of privatised firms were bought by bureaucrats and politicians and all firms were subjected to a period of supervision. We argue that the design of this process allowed rent-seekers to conserve their privileges through asset-stripping, which explains the failure. In order to do so, we perform an empirical analysis of the determinants of liquidation, merger and bankruptcy of privatised firms from 2002 to 2015. We construct a novel data set from primary sources, free of the ‘survivorship bias’ and containing proxies for various types of owners, indirect signs of asset-stripping strategy and a broad range of controls. Our results indicate that firms owned by politicians faced significantly higher risks of bankruptcy, especially after the end of supervision

TRIMETHYLTIN-induced differential expression of PAR subtypes in reactive astrocytes of the rat hippocampus.

Thrombin, its main inhibitor (protease nexin-1) and its related receptors (protease-activated receptors, PAR-1,-2, -3, -4) were studied in rat hippocampus following administration of trimethyltin (TMT), a neurotoxin inducing neuronal degeneration and reactive gliosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry revealed that while expression of prothrombin and protease nexin-1 did not change significantly in TMT-treated hippocampi, PARs (in particular PAR-I and to a lesser extent PAR-2 and PAR-3) were upregulated in reactive astrocytes, suggesting their involvement in neurodegeneration and in the consequent response of the nervous tissue

Trimethyltin-induced expression of protease-activated receptor-1 in rat microglia

Neuroinflammation is a prominent feature shared by various neurodegenerative diseases and it is important to identify the signal pathways that control the initiation, progression and termination of the inflammatory reaction since a well-regulated inflammatory process is essential for tissue homeostasis. Protease-activated receptors (PARs) are cleaved and activated by thrombin and other extracellular proteaseswhich are released during tissue trauma and inflammation. PAR-1 is the prototypic member of the PAR family and has been shown to be upregulated in several brain pathologies being expressed by neurons and glial cells. Our previous results show that PAR-1 expression is increased in astrocytes both in vivo and in vitro after treatment with the neurotoxic compound trimethyltin (TMT). Administration of TMT to the rat results in loss of hippocampal neurons and an ensuing gliosis without blood-brain barrier compromise. TMT caused pyramidal cell damage within 3 days and a substantial loss of these neurons by 21 days post dosing. Marked microglial activation and astrogliosis are evident over the same time period. TMT causes large increase of PAR-1 immunoreactivity in microglia by day 7 while in untreated controls this receptor is barely detectable. In vitro data show that the administration of the PAR-1 activating peptides (TRAP6 and TFLLR) inhibits the production of the pro-inflammatory cytokines TNF-alpha and IL-6 in microglial cells treated with lipopolysaccharide (LPS) while promoting the release of the anti-inflammatory cytokine IL-10. Our results suggest that PAR-1 may be involved in the regulation of the inflammatory response in the brain