Mercury Toxicity and Neurogenesis in the Mammalian Brain.

The mammalian brain is formed from billions of cells that include a wide array of neuronal and glial subtypes. Neural progenitor cells give rise to the vast majority of these cells during embryonic, fetal, and early postnatal developmental periods. The process of embryonic neurogenesis includes proliferation, differentiation, migration, the programmed death of some newly formed cells, and the final integration of differentiated neurons into neural networks. Adult neurogenesis also occurs in the mammalian brain, but adult neurogenesis is beyond the scope of this review. Developing embryonic neurons are particularly susceptible to neurotoxicants and especially mercury toxicity. This review focused on observations concerning how mercury, and in particular, methylmercury, affects neurogenesis in the developing mammalian brain. We summarized information on models used to study developmental mercury toxicity, theories of pathogenesis, and treatments that could be used to reduce the toxic effects of mercury on developing neurons.

Adult neurogenesis in the mammalian dentate gyrus.

Earlier observations in neuroscience suggested that no new neurons form in the mature central nervous system. Evidence now indicates that new neurons do form in the adult mammalian brain. Two regions of the mature mammalian brain generate new neurons: (a) the border of the lateral ventricles of the brain (subventricular zone) and (b) the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. This review focuses only on new neuron formation in the dentate gyrus of the hippocampus. During normal prenatal and early postnatal development, neural stem cells (NSCs) give rise to differentiated neurons. NSCs persist in the dentate gyrus SGZ, undergoing cell division, with some daughter cells differentiating into functional neurons that participate in learning and memory and general cognition through integration into pre-existing neural networks. Axons, which emanate from neurons in the entorhinal cortex, synapse with dendrites of the granule cells (small neurons) of the dentate gyrus. Axons from granule cells synapse with pyramidal cells in the hippocampal CA3 region, which send axons to synapse with CA1 hippocampal pyramidal cells that send their axons out of the hippocampus proper. Adult neurogenesis includes proliferation, differentiation, migration, the death of some newly formed cells and final integration of surviving cells into neural networks. We summarise these processes in adult mammalian hippocampal neurogenesis and discuss the roles of major signalling molecules that influence neurogenesis, including neurotransmitters and some hormones. The recent controversy raised concerning whether or not adult neurogenesis occurs in humans also is discussed.

Neural cell proliferation and survival in the hippocampus of adult CaV 2.1 calcium ion channel mutant mice.

Tottering mutant mice carry a mutation in the pore-forming subunit (α1A) of CaV2.1 (P/Q-type) voltage-gated calcium ion (Ca2+) channels resulting in reduced neuronal Ca2+ current density. We assessed male tottering mice for spatial learning using the Morris water maze. Tottering mice performed worse than wild type mice, suggesting abnormal hippocampal function. Because Ca2+ influx via voltage-dependent Ca2+ channels regulates neuronal survival and function, we assessed hippocampus volume and cell density using hematoxylin and eosin stained serial sections. Adult hippocampal neurogenesis was assessed using 5-bromo-2'-deoxyuridine (BrdU) labeling with fluorescent immunohistochemistry (IHC) and proliferating cell nuclear antigen (PCNA) with diaminobenzidine IHC. We double-labeled neurons using fluorescence IHC with BrdU-neuronal nuclei (Neu-N) or double labeling of astrocytes using BrdU-glial fibrillary protein, respectively, to assess cell proliferation and survival. We assessed numbers of dying cells using fluoro-Jade histochemistry. Decreased hippocampal volume, increased dentate hilar and hippocampal CA1 cell densities were observed in tottering mice compared to wild type mice. Cell proliferation was increased in the hilus and CA2 region of tottering mice compared to wild type mice. Dendritic intersections in Sholl analysis were decreased for tottering mouse CA1 pyramidal neurons compared to wild type mice. The increased regional cell density coincides with increases in cell proliferation in similar, non-neurogenic areas of the hippocampus of tottering mice. Thus, hippocampal alterations observed in adult tottering mice appear to result from changes in neuronal morphology and proliferation in non-neurogenic areas of the hippocampus, and less through altered adult hippocampal neurogenesis or cell death.

Circadian profiles in the embryonic chick heart: L-type voltage-gated calcium channels and signaling pathways.

Circadian clocks exist in the heart tissue and modulate multiple physiological events, from cardiac metabolism to contractile function and expression of circadian oscillator and metabolic-related genes. Ample evidence has demonstrated that there are endogenous circadian oscillators in adult mammalian cardiomyocytes. However, mammalian embryos cannot be entrained independently to light-dark (LD) cycles in vivo without any maternal influence, but circadian genes are well expressed and able to oscillate in embryonic stages. The authors took advantage of using chick embryos that are independent of maternal influences to investigate whether embryonic hearts could be entrained under LD cycles in ovo. The authors found circadian regulation of L-type voltage-gated calcium channels (L-VGCCs), the ion channels responsible for the production of cardiac muscle contraction in embryonic chick hearts. The mRNA levels and protein expression of VGCCα1C and VGCCα1D are under circadian control, and the average L-VGCC current density is significantly larger when cardiomyocytes are recorded during the night than day. The phosphorylation states of several kinases involved in insulin signaling and cardiac metabolism, including extracellular signal-regulated kinase (Erk), stress-activated protein kinase (p38), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK-3ß), are also under circadian control. Both Erk and p38 have been implicated in regulating cardiac contractility and in the development of various pathological states, such as cardiac hypertrophy and heart failure. Even though both Erk and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways participate in complex cellular processes regarding physiological or pathological states of cardiomyocytes, the circadian oscillators in the heart regulate these pathways independently, and both pathways contribute to the circadian regulation of L-VGCCs.

Phenolic glycosides from Lindera fruticosa root and their inhibitory activity on osteoclast differentiation.

Two new compounds were found in the phenolic glycosides isolated from the roots of Lindera fruticosa: 5-O-[beta-D-apiofuranosyl-(1''-->2')-O-beta-D-xylopyranosyl]gentisic acid-7,5''-ester (3), named linderofruticoside A; and 5-O-[beta-D-apiofuranosyl-(1''-->3')-O-beta-D-xylopyranosyl]gentisic acid methyl ester (4), linderofruticoside B. Two previously known phenolic glycosides were also identified: beta-D-(3,4-disinapoyl)fructofuranosyl-alpha-D-(6-sinapoyl)glucopyranoside (1) and beta-D-(3-sinapoyl)fructofuranosyl-alpha-D-(6-sinapoyl)glucopyranoside (2). Compounds 1 and 2 inhibited osteoclast differentiation in a dose-dependent manner at concentrations higher than 1.04 microM and 0.132 microM, respectively.

Phenolic compounds from the roots of Lindera fruticosa.

The phenolic compounds isolated from the roots of Lindera fruticosa included four new compounds, 2-methoxy-3,4-methylenedioxybenzophenone (1), (S)-2-methoxy-3,4-methylenedioxybenzhydryl alcohol (2), 3-hydroxy-5-methoxybiphenyl (3), and 1-methoxy-2,5,7-trihydroxyxanthone (4). Three previously identified phenolics were also identified, namely, 3,5-dimethoxybiphenyl (5), benzyl 2-hydroxy-6-methoxybenzoate (6), and 1,7-dihydroxyxanthone (7). These compounds were evaluated for their inhibitory effects on human acyl-CoA:cholesterol acyltransferase activity and on the in vitro oxidation of low-density lipoprotein.