ABSTRACT
Reelin is an extracellular matrix glycoprotein involved in the modulation of synaptic plasticity and essential for the proper radial migration of cortical neurons during development and for the integration and positioning of dentate granular cell progenitors; its expression is down-regulated as brain maturation is completed. Trimethyltin (TMT) is a potent neurotoxicant which causes selective neuronal death mainly localised in the CA1-CA3/hilus hippocampal regions. In the present study we analysed the expression of reelin and the modulation of endogenous neurogenesis in the postnatal rat hippocampus during TMT-induced neurodegeneration (TMT 6 mg/kg). Our results show that TMT administration induces changes in the physiological postnatal decrease of reelin expression in the hippocampus of developing rats. In particular, quantitative analysis of reelin-positive cells evidenced, in TMT-treated animals, a persistent reelin expression in the stratum lacunosum moleculare of Cornu Ammonis and in the molecular layer of Dentate Gyrus. In addition, a significant decrease in the number of bromodeoxyuridine (BrdU)-labeled newly-generated cells was also detectable in the subgranular zone of P21 TMT-treated rats compared with P21 control animals; no differences between P28 TMT-treated rats and age-matched control group were observed. In addition the neuronal commitment of BrdU-positive cells appeared reduced in P21 TMT-treated rats compared with P28 TMT-treated animals. Thus TMT treatment, administrated during development, induces an early reduction of endogenous neurogenesis and influences the hippocampal pattern of reelin expression in a temporally and regionally specific manner, altering the physiological decrease of this protein.
Subject(s)
Cell Adhesion Molecules, Neuronal/biosynthesis , Extracellular Matrix Proteins/biosynthesis , Gene Expression Regulation, Developmental , Hippocampus/growth & development , Hippocampus/metabolism , Nerve Tissue Proteins/biosynthesis , Neurogenesis/physiology , Serine Endopeptidases/biosynthesis , Trimethyltin Compounds/pharmacology , Animals , Animals, Newborn , Cell Adhesion Molecules, Neuronal/antagonists & inhibitors , Cell Adhesion Molecules, Neuronal/genetics , Extracellular Matrix Proteins/antagonists & inhibitors , Extracellular Matrix Proteins/genetics , Gene Expression Regulation, Developmental/drug effects , Hippocampus/drug effects , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Neurogenesis/drug effects , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Rats , Rats, Wistar , Reelin Protein , Serine Endopeptidases/geneticsABSTRACT
The effects of intracerebroventricular administration of neuropeptide Y (NPY), which is believed to play an important role in neuroprotection against excitotoxicity and in the modulation of adult neurogenesis, were evaluated in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy represented by trimethyltin (TMT) intoxication. A single TMT injection (8 mg/kg) causes, in the rat brain, massive neuronal death, selectively involving pyramidal neurons, accompanied by glial activation and enhanced hippocampal neurogenesis. Our data indicate that intracerebroventricular administration of exogenous NPY (at the dose of 2 µg/2 µL, 4 days after TMT-administration), in adult rats, exerts a protective role in regard to TMT-induced hippocampal damage and a proliferative effect on the hippocampal neurogenic niche through the up-regulation of Bcl-2, Bcl2l1, Bdnf, Sox-2, NeuroD1, Noggin and Doublecortin genes, contributing to delineate more clearly the role of NPY in in vivo neurodegenerative processes.
Subject(s)
Epilepsy, Temporal Lobe/drug therapy , Epilepsy, Temporal Lobe/pathology , Hippocampus/drug effects , Nerve Degeneration/prevention & control , Neurogenesis/drug effects , Neuropeptide Y/pharmacology , Neuroprotective Agents , Trimethyltin Compounds , Animals , Antimetabolites , Apoptosis Regulatory Proteins/biosynthesis , Brain-Derived Neurotrophic Factor/biosynthesis , Bromodeoxyuridine , Doublecortin Protein , Epilepsy, Temporal Lobe/chemically induced , Female , Gene Expression/drug effects , Hippocampus/pathology , Immunohistochemistry , Injections, Intraventricular , Nerve Degeneration/etiology , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neurogenesis/genetics , Neuropeptide Y/administration & dosage , RNA/biosynthesis , RNA/isolation & purification , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction , Receptors, Neuropeptide Y/drug effectsABSTRACT
Cancer might result from both the aberrant activation of genes, whose physiological tuning is essential for the life of a normal cell, and the inactivation of tumor suppressor genes, whose main job is to preserve the integrity of cell genome. Among the latter, p53 is considered a key tumor suppressor gene that is inactivated mainly by missense mutations in half of human cancers. It is becoming increasingly clear that the resulting mutant p53 proteins gain oncogenic properties favoring the insurgence, the maintenance, and the spreading of malignant tumors. In this review, we mainly discuss the molecular mechanisms underlying gain of function of human tumor-derived p53 mutants, their impact on the chemoresistance and the prognosis of human tumors, with a special focus on head and neck cancers, and the perspectives of treating tumors through the manipulation of mutant p53 proteins.
