In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper͞zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin͞iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy-and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper͞zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. L ocus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism, and memory (1, 2), whereas the spinal cord projections are known to modulate spinal motoneuron function (3, 4).Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5, 6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5-8). However, a recent study reported extensive impairment of LC neurons in PD (9). SN and LC share anatomical and biochemical similarities, being both pigmented because of neuromelanin (NM), and both composed of catecholaminergic neurons. Yet, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineintoxicated subjects, LC neurons are spared, whereas a large neuronal depletion occurs in SN (10, 11). Also, in other types of Parkinsonian syndromes caused by exposure to toxins, the LC neurons seem less damaged than those of...

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X-ray absorption fine-structure spectroscopy is used to study the local environment of the iron site in natural (human) neuromelanin extracted from substantia nigra tissue and in various synthetic neuromelanins. All the materials show Fe centered in a nearest neighbor sixfold (distorted) oxygen octahedron; the Fe-O distances, while slightly different in the natural and synthetic neuromelanin, are both approximately 2.0 A. Appreciable differences arise, however, in the second (and higher) coordination shells. In this case the synthetic melanin has the four planar oxygens bound to carbon rings with Fe-C distances of approximately 2.82 and 4.13 A; the human sample does not show the 2.82 A link but instead indicates a double shell at approximately 3.45 and 3.78 A.

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Brain-derived neurotrophic factor (BDNF) regulates several properties of striatal dopaminoceptive medium-sized spiny neurons (MSNs) in vivo and in vitro, including expression levels of DARPP-32 (dopamine and cyclic adenosine 3 H ,5 Hmonophosphate-regulated phosphoprotein, 32 kDa). DARPP-32 is expressed in 96% of the MSNs, and is a key modulator of dopamine actions. We investigated the intracellular signal transduction pathways activated by BDNF in MSNs and via which BDNF induces DARPP-32 expression. We found that phosphorylation of the cyclic AMP response element binding protein (CREB) is only transiently increased following stimulation of MSNs by BDNF, whereas increased phosphorylation of the extracellular signal regulated kinases 1 and 2 (Erk1/2) and Akt is sustained for longer than 4 h. Treatment of cultures with inhibitors of mitogen-activated protein kinase kinase (MEK) or phosphatidylinositide 3-kinase (PI3K) showed that the majority of the BDNF-induced increase in DARPP-32 requires the PI3K pathway. We also found that inhibition of PI3K reduces BDNF-induced Erk phosphorylation, indicating that cross-talk between these pathways may play a prominent role in MSNs.

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Gender differences exist in the development of the nigrostriatal dopamine system, and in the incidence and course of pediatric and adult neuropsychiatric diseases in which this system is implicated. The medium size spiny neuron (MSN) is the major output neuron of the caudate nucleus. It receives a large dopaminergic input from the substantia nigra, and 96% of the MSNs express DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein and key mediator of dopamine function. There are few examples, however, of direct effects of sex hormones, including 17β-estradiol (E₂), on the MSN. We report that in vitro, E₂ (10–50 nM) promotes MSN phenotypic maturation, as determined by increased soma size, neurite length, and DARPP-32 protein levels. Treatment with the ‘anti-estrogen’ ICI 182,780 or the partial-agonist tamoxifen also increases DARPP-32 levels, but when added to E₂, ICI 182,780 only prevents the increase in DARPP-32 levels and increase in soma size and neurite length. Surprisingly, maturation effects are more robust in cells derived exclusively from female embryos. Western blot analysis of protein lysates and immunocytochemistry of cultured MSNs reveals the presence of the estrogen receptor β (ERβ). These data suggest that ERβ may mediate the differentiating effect of E₂ on embryonic MSNs, and provide new avenues of investigation for the role of sex hormones in the development of the striatum and in diseases affecting the basal ganglia.