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PubMed1988

Postnatal development of parvalbumin-, calbindin- and adult GABA-immunoreactivity in two visual nuclei of zebra finches.

The characterization of neuron populations by their immunoreactivity against parvalbumin- and calbindin (28-kDa)-antisera has been used to study the postnatal development of the visual diencephalic nucleus rotundus and the mesencephalic nucleus isthmi complex in zebra finches. In nucleus rotundus, parvalbumin-immunoreactivity was restricted to the neuropil during the first 10 days and appears additionally in somata around day 12 where it remains until adulthood. Calbindin-immunoreactivity of the very scarce neuropil and the few somata, which can be observed during the first two weeks, disappears until adulthood. Thus, the adult nucleus rotundus shows an almost complementary distribution of calbindin- and parvalbumin-immunoreactive structures: the numerous, heavily parvalbumin-positive somata, which are surrounded by dense immunoreactive neuropil are in sharp contrast to the complete absence of calbindin-immunoreactive somata. Only a thin rim surrounding this nucleus contains punctate calbindin-positive neuropil. In the nucleus isthmi complex, parvalbumin and calbindin staining patterns show markedly different developmental profiles. While the density of parvalbumin-immunoreactive neuropil in the parvocellular part of the nucleus isthmi continuously increases and the somata remain unstained, the initially heavily calbindin-positive somata gradually lose their immunoreactivity during the first two weeks. In the adult nucleus isthmi complex, parvalbumin- and calbindin show nearly identical staining patterns. A comparison between the two calcium-binding proteins and GABA-immunoreactivity in adult brains revealed different relationships in the two nuclei: while in nucleus rotundus GABA-staining pattern neither resembles that of parvalbumin nor of calbindin, in the nucleus isthmi complex all three staining patterns coincide.

Animals↗
PubMed1991

Sensitive enzyme immunoassay for human 28 kDa calbindin-D.

A sandwich-type enzyme immunoassay for human 28 kDa vitamin D-dependent calcium binding protein (calbindin-D) was established with a sensitivity of 1 pg/tube. Antisera were generated in rabbits injected with highly purified human kidney calbindin-D, and specific antibodies to calbindin-D were purified by the use of a column of calbindin-D-coupled Sepharose. The purified antibodies showed a single band at the position corresponding to calbindin-D on an immunoblotting test with a crude extract of human kidney. The assay system consisted of polystyrene balls with immobilized F(ab')2 antibodies and the same antibodies labeled with beta-D-galactosidase from Escherichia coli. The assay was specific to 28 kDa calbindin-D, showing no cross-reactivity with other calcium binding proteins such as S-100a0 (alpha alpha), S-100b (beta beta), parvalbumin and calmodulin. The assay was also reproducible (coefficients of variation between assays were less than 10%). With the present method, immunoreactive calbindin-D could be detected in various human tissues, with major concentrations in kidney and brain. The values for immunoreactive calbindin-D in various body fluids of healthy subjects varied from undetectable in serum and semen to 3.8 +/- 2.0 (SD) micrograms/g creatinine in urine and 2.9 +/- 0.8 (SD) micrograms/l in cerebrospinal fluid. Immunohistochemically, the calbindin-D in human kidney was localized in epithelial cells of distal tubules.

Adult↗
PubMed1990

Calbindin D-28k and parvalbumin in the rat nervous system.

This paper describes the distribution of structures stained with mono- and polyclonal antibodies to the calcium-binding proteins calbindin D-28k and parvalbumin in the nervous system of adult rats. As a general characterization it can be stated that calbindin antibodies mainly label cells with thin, unmyelinated axons projecting in a diffuse manner. On the other hand, parvalbumin mostly occurs in cells with thick, myelinated axons and restricted, focused projection fields. The distinctive staining with antibodies against these two proteins can be observed throughout the nervous system. Calbindin D-28k is primarily associated with long-axon neurons (Golgi type I cells) exemplified by thalamic projection neurons, strionigral neurons, nucleus basalis Meynert neurons, cerebellar Purkinje cells, large spinal-, retinal-, cochlear- and vestibular ganglion cells. Calbindin D-28k occurs in all major pathways of the limbic system with the exception of the fornix. Calbindin D-28k is, however, also found in some short-axon cells (Golgi type II), represented by spinal cord interneurons in layer II and interneurons of the cerebral cortex. It is also detectable in some ependymal cells and abundantly occurs in vegetative centres of the hypothalamus. The "paracrine core" of the nervous system and its adjunct (1985, Nieuwenhuys, Chemoarchitecture of the Brain. Springer, Berlin) is very rich in calbindin D-28k. The distribution of calbindin D-28k-positive neurons is very similar to that of the dihydroperydine subtype of calcium channels. Most of the cells containing calbindin D-28k are vulnerable to neurodegenerative processes. Parvalbumin-immunoreactive neurons have a different, and mostly complementary distribution compared with those which react with calbindin D-28k antisera, but in a few cases (Purkinje cells of the cerebellum, spinal ganglion neurons), both calcium-binding proteins co-exist in the same neuron. Many parvalbumin-immunoreactive cells in the central nervous system are interneurons (Golgi type II) and, to a lesser extent, long-axon cells (Golgi type I), whereas conditions are vice versa in the peripheral nervous system. Intrinsic parvalbuminic neurons are prominent in the cerebral cortex, hippocampus, cerebellar cortex and spinal cord. Long-axon parvalbumin-immunoreactive neurons are, for example, the Purkinje cells, neurons of the thalamic reticular nucleus, globus pallidus, substantia nigra (pars reticulata) and a subpopulation among large spinal-, retinal-, cochlear- and vestibular ganglion cells. Parvalbumin is rich in cranial nerve nuclei related to eye movements. In addition to nervous elements, parvalbumin immunoreactivity occurs in a few ependymal cells and in some pillar cells of the organ of Corti.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Effect of age and dietary calcium on intestinal calbindin D-9k expression in the rat.

The capacity of rats and humans to adapt to low dietary Ca by increasing intestinal Ca absorption declines with age. The intestinal calbindin-D-9k protein (calbindin) is thought to play a role in the transcellular transport of Ca across the mammalian intestine. The purpose of these studies was to determine the effect of age and diet on the expression of calbindin at the protein and mRNA levels. Young (2 month) and adult (12 month) male F344 rats were placed on either a high Ca diet (1.2%) or a low Ca diet (0.02%) for four weeks. In the duodenum, the level of intestinal calbindin protein induced by a low Ca diet was 8-fold higher in young rats compared to adult rats. In the ileum, expression of calbindin protein was only about 10% that of the duodenum. In addition, the adult ileum showed the same decreased adaptation to a low Ca diet that was seen in the adult duodenum. In both the duodenum and the ileum, the changes in calbindin protein expression were highly correlated with calbindin mRNA expression and the correlations in each segment were quantitatively similar. In the duodenum, the changes in calbindin protein levels were strongly correlated with both Ca transport and Ca uptake. This quantitative correlation suggests a role for calbindin protein in the age-related decline in Ca absorption. In the ileum, the decreased adaptation to a low Ca diet may also be important given the long transit time through the distal intestine. The changes in both intestinal segments may contribute to the negative Ca balance seen in adult rats fed a low Ca diet.

Adaptation, Physiological↗
PubMed1993

Increased levels of calbindin-D in serum and urine from patients treated by extracorporeal shock wave lithotripsy.

Calbindin-D 28 kDa. is a vitamin D-dependent calcium binding protein that is found mainly in the distal renal tubules and central nervous tissue in humans. Calbindin-D was measured in the serum and urine before, and immediately, 2 hours or 24 hours after extracorporeal shock wave lithotripsy (ESWL*) in 83 consecutive patients. ESWL was performed with the Siemens Lithostar device in 61 patients and with the Dornier MPL9000 lithotriptor in 22. The serum 28 kDa. calbindin-D level was undetectable (less than 20 pg./ml.) in many samples, whereas urinary 28 kDa. calbindin-D could be detected in every sample. The serum 28 kDa. calbindin-D level was usually elevated after ESWL and the concentration in patients treated with the MPL9000 device was greater than in those treated with the Lithostar instrument. Urinary 28 kDa. calbindin-D levels were elevated significantly immediately and at 2 hours after ESWL, and they decreased to the baseline level within 24 hours after ESWL in the Lithostar group but remained consistently significantly elevated after ESWL in the MPL9000 group. This fact may be because the MPL9000 lithotriptor produces a stronger shock wave than does the Lithostar device during ESWL. These results suggest that 28 kDa. calbindin-D is released from damaged distal renal tubule cells into the serum and urine during ESWL and that 28 kDa. calbindin-D is a specific marker for renal damage by ESWL. To our knowledge this is the first clinical study using a sensitive enzyme immunoassay for human 28 kDa. calbindin-D to estimate renal damage during ESWL.

Adult↗
PubMed1989

Gestational changes in calbindin-D9k in rat uterus, yolk sac, and placenta: implications for maternal-fetal calcium transport and uterine muscle function.

Calbindin-D9k was quantified and its cellular location was defined in uterus, yolk sac, and placenta. In late gestation (days 17 to term) coordinated induction of calbindin-D9k was seen in uterine epithelial lining cells and juxtaposed yolk sac visceral epithelium as well as the intraplacental yolk sac epithelium. The induction of calbindin-D9k in these cells coincided with the time of exponential fetal bone growth and maximal fetal accumulation of calcium, suggesting a role of the protein in these epithelial layers in maternal-fetal calcium transport. Dynamic changes also occurred in the calbindin-D9k contents of the two layers of uterine smooth muscle (outer longitudinal and inner circular) during mid- and late gestation. During early pregnancy (days 0-4), calbindin-D9k was present in the two smooth muscle layers. By midgestation (day 10), calbindin-D9k had decreased by a factor of 10 in these tissue layers. During late gestation calbindin-D9k rebounded in the inner circular smooth muscle layer. These uterine changes of early and midgestation were reproduced by the endocrine changes of pseudopregnancy. Progesterone appeared to be a good candidate for controlling the midgestational decrease of uterine muscle calbindin-D9k, as it blunted estrogen's induction of the protein in the muscle layers and stroma in a dose-dependent manner. Changes in myometrial calbindin-D9k may reflect variations in muscular calcium storage, thereby representing alterations in potential for contraction.

Animals↗
PubMed1991

Developmental control over vitamin-D-induced calbindin gene expression during early differentiation of chicken jejunal enterocytes.

In situ hybridization and immunocytochemical techniques have been used to examine the distribution of vitamin-D-induced calbindin mRNA and calbindin protein in enterocytes lining the crypts and villi of chicken small intestine. Basal villus enterocytes contained approximately twice as much calbindin but over three times as much calbindin mRNA compared to values found in basal crypt and upper villus enterocytes, all values being measured 2 days after vitamin D injection into D-deficient chickens. Virtually no calbindin mRNA was detected in tissues taken from control D-deficient birds. Direct proportionality found between calbindin mRNA and calbindin content in enterocytes of basal crypt, mid and upper villus suggests pre-translational control over calbindin synthesis. The implications of possible inefficient translation of calbindin mRNA in basal villus enterocytes are discussed. Present methods of analysis provide a novel way to study mechanisms controlling gene expression throughout the whole process of enterocyte differentiation.

Animals↗
PubMed1996

Urinary 28-kD calbindin-D as a new marker for damage to distal renal tubules caused by cisplatin-based chemotherapy.

Calbindin-D, a vitamin D-dependent calcium-binding protein of 28 kD, is found predominantly in the distal tubules of the kidney and central nervous system tissues in humans. To evaluate damage to the renal tubules caused by cisplatin-based chemotherapy, levels of urinary and serum calbindin-D were determined in patients treated with cisplatin- or carboplatin-based chemotherapies using a highly sensitive enzyme immunoassay system developed in our laboratory. Levels of urinary 28-kD calbindin-D were also determined in patients with benign and malignant urological diseases. The mean urinary calbindin-D level was 2.44 + or - 0.31 (mean + or - SE) ng/mg creatinine in 40 healthy subjects. Urinary calbindin-D levels were elevated (>10 ng/mg creatinine) in 2 of 33 patients (6%) with benign and 1 of 50 (2%) with malignant urological diseases. Urinary calbindin-D levels were significantly increased after cisplatin-based chemotherapy in 14 patients, with peaks (71.8 + or - 13.5 ng/mg creatinine) being found 8 days after administration of cisplatin, and then a gradual return to the baseline. On the other hand, 7 patients receiving carboplatin-based chemotherapy demonstrated no significant elevation (highest level 7.7 + or - 2.5 ng/mg creatinine). In 7 patients treated with cisplatin-based chemotherapy the serum calbindin-D level was also raised after treatment, with a good correlation to urinary values. These findings suggest that urinary and serum calbindin-D may be kidney-derived and that 28-kDa calbindin-D is a useful marker for damage to the distal renal tubules associated with cisplatin-based chemotherapy.

Acetylglucosaminidase↗
PubMed1997

Androgen mitigates axotomy-induced decreases in calbindin expression in motor neurons.

Androgens can rescue axotomized motor neurons from cell death. Here we examine a possible mechanism for this trophic action in juvenile Xenopus laevis: regulation of a calcium-binding protein, calbindin, after axotomy. Western analysis revealed that a monoclonal antibody to calbindin D specifically recognizes a single approximately 28 kDa band in X. laevis CNS and rat cerebellum. Retrograde transport of peroxidase combined with immunohistochemistry demonstrated that somata, axons, and synaptic terminals of laryngeal motor neurons in nucleus (N.) IX-X of X. laevis are calbindin-positive. The number of calbindin-positive cells was compared in the intact and axotomized sides of N.IX-X of gonadectomized males that were either hormonally untreated or DHT-treated for 1 month. Although axotomy decreased the number of calbindin-positive cells by 86% in hormonally untreated males, the decrease was only 56% in DHT-treated animals. Compared with hormonally untreated animals, the number of calbindin-labeled cells in N.IX-X of DHT-treated males was increased in both the intact (14%) and axotomized sides (75%). We conclude that axotomy decreases and that DHT enhances calbindin immunoreactivity in N.IX-X. Axotomy-induced decrease in calbindin immunoreactivity precedes cell loss in N.IX-X and may impair the capacity of motor neurons to regulate cytoplasmic calcium. Androgen-mediated maintenance of calbindin expression is thus a candidate cellular mechanism for trophic maintenance of hormone target neurons.

Animals↗
PubMed1990

Calbindin and calretinin localization in retina from different species.

Calbindin-D28K and calretinin are homologous calcium-binding proteins localized in many neurons of the central nervous systems. We have compared polyclonal antibodies against calbindin and calretinin and have shown by western blots using purified calbindin and calretinin from rat that (1) anti-calretinin does not recognize calbindin and (2) anti-calbindin presents some cross-reactivity with calretinin. In this report, we have compared by immunohistochemistry the localization of both calcium-binding proteins in the retina of monkey, pig, sheep, rat, cat, pigeon, and salamander. These results are compared with previous data for chick. There are many differences between species and not within species, but some aspects of the distribution are conserved. All species, except rat and monkey, have some cones which contain calbindin only. Most species also have some bipolar cells containing calbindin only. Calretinin is rarely seen in photoreceptors or bipolar cells. All species have horizontal cells which contain calretinin or calbindin or both. All species have amacrine cells and ganglion cells containing one or other protein. In the cat ganglion cell layer, the calretinin antisera define a new, asymmetric, type of cell.

Animals↗
PubMed2004

Effect of calbindin-D28K on cyclosporine toxicity in cultured renal proximal tubular cells.

Cyclosporine A (CsA) is known to have direct toxicity to renal tubular cells. Its toxicity may be mediated by intracellular calcium because CsA increases intracellular calcium concentration and enhances the activities of calcium-dependent calpains and caspases. Calbindin-D28k, a cytosolic calcium binding protein, has been used as an intracellular Ca2+ buffer to reduce calcium-mediated cytotoxicity in non-renal cells such as neuronal cells. We investigated the effects of gene transfer of calbindin-D28k cDNA on CsA cytotoxicity and intracellular calcium concentration ([Ca2+]i) in cultured murine proximal tubular (MCT) cells. A plasmid containing calbindin-D28k cDNA under the control of CMV promoter was transfected to MCT cells with liposomes. Cytotoxicity was assessed by LDH release and cell viability assay, and [Ca2+]i was measured ratiometrically with fura-2. Compared with MCT cells, cells transfected with calbindin-D28k cDNA showed a reduction in LDH release by 27, 30, 32, 33, and 19% (all P < 0.05), respectively, after 24 h exposure to 1, 2.5, 5, 10, and 25 microM CsA. Cell viability after CsA treatment was also significantly higher in CB cells. A mock transfection using plasmid without calbindin-D28k cDNA insert did not affect the LDH release or cell viability after CsA treatment. CsA treatment did not affect the protein and mRNA abundance of transfected calbindin-D28k cDNA. The expression of calbindin-D28k did not affect the baseline [Ca2+]i, but significantly suppressed CsA-induced elevation in [Ca2+]i. The expression of calbindin-D28k in renal tubular cells provides cytoprotective effects against CsA toxicity, probably through its buffering effects on [Ca2+]i.

Animals↗
PubMed1989

Analysis of parvalbumin and calbindin D28k-immunoreactive neurons in dorsal root ganglia of rat in relation to their cytochrome oxidase and carbonic anhydrase content.

Histochemical and immunohistochemical techniques were used to determine relationships between the parvalbumin or calbindin D28k content and the cytochrome oxidase or carbonic anhydrase activity of neurons in lumbar dorsal root ganglia in rat. Subpopulations of dorsal root ganglion neurons that displayed parvalbumin- or calbindin D28k-immunoreactivity were classified as containing either light, moderate or dense histochemical reaction product for cytochrome oxidase and either a positive or negative reaction for carbonic anhydrase. It was found that approximately 90% of all parvalbumin and calbindin D28k-immunoreactive cells exhibited dense staining for cytochrome oxidase and that 87% of parvalbumin- and 76% of calbindin D28k-immunoreactive cells were positive for carbonic anhydrase. Conversely, 85% of all cells with a dense cytochrome oxidase reaction contained parvalbumin and calbindin D28k. Although not quantified, it appeared that many, but not all, carbonic anhydrase-positive cells contained parvalbumin or calbindin D28k. These results indicate the existence of a subpopulation of primary sensory neurons that contains parvalbumin and calbindin D28k and that expresses high levels of cytochrome oxidase and carbonic anhydrase activity. It is suggested that primary afferent neurons with this cytochemical profile transmit a sensory modality that requires them to discharge rapidly and/or frequently. The existence of a subpopulation of carbonic anhydrase-positive cells that lack immunoreactivity for parvalbumin or calbindin D28k suggests that the role of carbonic anhydrase in some sensory neurons is unrelated to functions requiring these calcium binding proteins.

Animals↗
PubMed1992

Calbindin D28k-containing nonpyramidal cells in the rat hippocampus: their immunoreactivity for GABA and projection to the medial septum.

Calbindin D28k-containing non-pyramidal cells were found in all layers and subfields of the hippocampus, with the highest frequency in stratum radiatum of the CA1-CA3 subfields. A large number of these neurons had a vertically oriented dendritic tree, often restricted to to stratum radiatum. In stratum oriens and near to the border of strata radiatum and lacunosum moleculare cells with horizontally running dendrites were also found. Multipolar cells were most common in stratum radiatum of the CA3 region. The GABAergic nature of the calbindin D28k-containing non-pyramidal cells was studied using the "mirror" technique. Adjacent thick sections were immunostained for calbindin D28k and GABA, and halved neurons were identified on the common surfaces. The majority of calbindin D28k-containing non-pyramidal cells were shown to be GABAergic. The GABA-negative calbindin cells were found in relatively large numbers in stratum oriens of the CA1-CA3 region, and occasionally in strata radiatum and pyramidale of CA2, and in stratum radiatum of the CA3c region near to the border of the dentate hilus. However, even in these cells a weak immunostaining, only slightly but consistently above background level, was always observed. Earlier studies have demonstrated that the somata of GABAergic neurons with distant projections may contain a level of GABA that is below the detection threshold of immunocytochemistry. Here we provide direct evidence that the calbindin-containing non-pyramidal cells were among those projecting to the medial septum. Following horseradish peroxidase injections into the medial septum 80% of the retrogradely labelled non-pyramidal cells were found to be immunoreactive for calbindin D28k, and 20% contained neuropeptide Y. These results suggest that the calbindin D28k-containing and apparently GABA-immunonegative non-pyramidal cells in stratum oriens of the CA1-CA3 regions may also be GABAergic, but have a distant projection, that is, to the medial septum.

Animals↗
PubMed1994

Sparing of the dopaminergic neurons containing calbindin-D28k and of the dopaminergic mesocortical projections in weaver mutant mice.

In mice carrying the weaver mutation there is a spontaneous degeneration of dopaminergic neurons that is heterogeneous among cell groups: nigrostriatal neurons are more affected than mesolimbic neurons, while involvement of the mesocortical system is controversial. We questioned whether the pattern of cell loss in mesencephalon and fiber depletion in telencephalon could be related to the differential content of Calbindin-D28k in dopaminergic cells. The mesencephalon of seven-month-old mutants was serially sectioned and alternate series were immunostained with tyrosine hydroxylase and Calbindin-D28k. Cell counts indicated a 40% loss for the ensemble of dopamine mesencephalic neurons. However, double-immunostained preparations revealed that this cell loss was restricted to the neurons that lacked Calbindin-D28k, which were reduced by 72%, while the dopaminergic neurons containing Calbindin-D28k were completely spared. Calbindin-D28k was present in both the cytoplasm and nucleus of the dopaminergic cells. This nuclear localization was confirmed at the ultrastructural level. In the telencephalon of weaver mutants, areas receiving projections from the Calbindin-D28k-positive dopaminergic neurons, such as the cerebral cortex, contained normal densities of fibers, while areas harboring projections from the non-Calbindin-D28k dopaminergic neurons, such as the dorsal striatum, had reduced amounts of fibers. The vulnerability pattern in the mesencephalon of weaver mutants bears similarities to that described in idiopathic Parkinson's disease or in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism: Calbindin-D28k may thus delimit a group of dopaminergic neurons resistant to cell death in different conditions. On the other hand, the vulnerability pattern of dopaminergic fibers in weaver differs from that of Parkinson's disease, since there is a complete sparing of the dopaminergic mesocortical projection in weaver, contrasting with the damage of these projections in Parkinson's disease.

Afferent Pathways↗
PubMed1996

Calbindin-D28K-immunoreactive cells and fibres in the human amygdaloid complex.

The distribution of calbindin-D28k-immunoreactive cells and fibres in five human amygdalae was analysed from sections that had been stained immunohistochemically with a monoclonal antibody raised against calbindin-D28k. The highest density of calbindin-D28k-positive neurons were found in the anterior cortical, medial, posterior cortical and accessory basal nuclei, in the parvicellular division of the basal nucleus and in the amygdalohippocampal area. The lowest densities of immunopositive neurons were found in the paralaminar nucleus, in the periamygdaloid cortex (PAC1 and PACo) and in some of the intercalated nuclei. The deep nuclei (lateral, basal and accessory basal nuclei) contained a high density of calbindin-D28k-immunoreactive fibres and terminals. The cortical nuclei and the central nucleus were characterized by intense neuropil labelling. Morphologically, a large majority of the calbindin-D28k-immunoreactive neurons were aspiny or sparsely spiny and resembled inhibitory local circuit neurons. A small population of lightly-stained, pyramidal-shaped neurons was also observed. In most of the amygdaloid nuclei, calbindin-D28k-immunoreactive fibres travelled close to each other and formed bundles, which suggests that some of the immunostained neurons were double-bouquet cells. In the paralaminar nucleus, the calbindin-D28k-immunoreactive axons formed tortuous plexus (100-200 microns in diameter) that surrounded several unstained somata. This study provides baseline information on the morphology and distribution of calcium-binding protein-containing inhibitory cells and fibres immunoreactive for calbindin-D28k in the human amygdaloid complex. This information can be used in future studies on the pathogenesis of diseases known to damage the amygdala, such as Alzheimer's disease and temporal lobe epilepsy.

Adult↗
PubMed2005

Increased calbindin-D28k immunoreactivity in striatal projection neurons of R6/2 Huntington's disease transgenic mice.

Striatal degeneration in Huntington's disease (HD) is associated with increases in perikaryal calbindin immunolabeling in yet-surviving striatal projection neurons. Since similar increases have also been observed in surviving striatal projection neurons after intrastriatal injection of the excitotoxin quinolinic acid, the increased calbindin in HD striatum has been interpreted to suggest an excitotoxic process in HD. We used immunolabeling to assess if calbindin is elevated in striatal projection neurons of R6/2 HD transgenic mice. These mice bear exon 1 of the human huntingtin gene with 144 CAG repeats and show some of the neuropathological signs (e.g., neuronal intranuclear inclusions) and clinical traits (e.g., wasting prior to early death) of HD. We found an increased frequency of calbindin-immunoreactive neuronal perikarya in the striatum of 6- and 12-week-old R6/2 mice compared to wild-type controls. This increase was most notable in the normally calbindin-poor dorsolateral striatum. We found no significant changes in the total area of striatum occupied by the calbindin-negative striosomes and no consistent changes in striatal calbindin mRNA. The increase in calbindin in R6/2 striatal neurons was thus limited to the matrix compartment, and it may be triggered by increased Ca2+ entry due to the demonstrated heightened NMDA sensitivity of these neurons. The data further support the similarity of R6/2 mice to HD, and are consistent with the occurrence of an excitotoxic process in striatum in both.

Animals↗
PubMed2000

Calbindin-D28k in cerebrovascular extrinsic innervation system of the rat.

Calbindin-D28k, one of the calcium-binding proteins, belongs to the EF hand family and is commonly found in neurons. It serves as a representative neuronal marker for neuroanatomical investigations. The authors' knowledge of its precise function, however, is yet very limited. In this study, we examined the existence of nerve fibers with calbindin-D28k immunoreactivity in the cerebral blood vessels and ganglia that innervate the cerebral blood vessels in the rat. Numerous nerve fibers with calbindin-D28k immunoreactivity were observed on the walls of the major extracerebral arteries forming the circle of Willis and its branches. Calbindin-D28k immunoreactivity was seen in many neurons of the trigeminal, dorsal root and jugular ganglia. A small number of neurons showed calbindin-D28k immunoreactivity in the otic and superior cervical ganglia. Calbindin-D28k immunoreactivity was not detected in the sphenopalatine or internal carotid ganglia. Pericellular basket-like formations of nerve terminals with calbindin-D28k immunoreactivity were observed in the sphenopalatine, otic, internal carotid and superior cervical ganglia. The present study demonstrated calbindin-D28k immunoreactivity in the cerebrovascular nerve fibers as well as in their origins--the cranial ganglia. These findings are significant in understanding the calcium-mediated mechanism of the neural control of the cerebral blood vessels.

Animals↗
PubMed2002

Cyclosporine A-induced hypercalciuria in calbindin-D28k knockout and wild-type mice.

BACKGROUND: It is known that cyclosporine A (CsA) treatment induces high bone-turnover osteopenia and hypercalciuria. It has been proposed that down-regulation of renal calbindin-D28k by CsA results in renal calcium wasting. We investigated the role of the kidney and bone in CsA-induced hypercalciuria in calbindin-D28k knockout (KO) and wild-type (WT) mice. METHODS: Two sets of experiments were performed. In experiment 1, KO and WT mice were treated with CsA 20 mg/kg/day intraperitoneally (IP) for 7 days. In experiment 2, to eliminate the CsA effect on bone resorption, pamidronate (APD) 2.5 mg/kg IP was given every 4 days with the first dose given 4 days prior to the 7-day course of CsA. Serum levels of creatinine, calcium, and osteocalcin, as well as renal calcium excretion were measured to assess CsA's effects on calcium homeostasis. Effects of CsA on the expression of calbindin-D28k, and two calcium channels in the apical membrane of the distal tubule, epithelial calcium channel (ECaC) and alpha1G-subunit of a voltage-dependent Ca channel (alpha1G), in the kidney were examined by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: KO mice had a threefold increase in renal calcium excretion when compared with WT mice at the baseline. This difference disappeared when calcium load was reduced by overnight fasting. After the CsA treatment, both WT and KO mice had a significant increase of renal calcium excretion (urine Ca/Cr ratio in WT, 0.11 +/- 0.01 to 1.29 +/- 0.17; in KO, 0.39 +/- 0.04 to 1.18 +/- 0.13; both P < 0.01). CsA treatment decreased renal calbindin-D28k mRNA by 61%, but did not affect the expression of ECaC and alpha1G. Baseline serum osteocalcin level of KO mice was significantly lower than that of WT mice. After CsA treatment, both groups had a 50% increase in the serum osteocalcin level, indicating increased bone turnover. When mice were treated with both CsA and APD, the increase in serum osteocalcin level was prevented, and renal calcium excretion was significantly lower than that in mice treated with CsA alone. However, there was still a significant increase in the urine Ca/Cr ratio in WT and KO mice compared with pretreatment levels (urine Ca/Cr in WT, 0.11 +/- 0.01 to 0.76 +/- 0.05, P < 0.01; in KO, 0.39 +/- 0.05 to 0.79 +/- 0.06; P < 0.01). CONCLUSION: Calbindin-D28k KO mice have diet-dependent hypercalciuria and a lower bone turnover rate. CsA treatment suppresses the expression of calbindin-D28k in mice, but has no effects on ECaC and alpha1G gene expression at the mRNA level. The pathogenesis of CsA-induced hypercalciuria involves both down-regulation of calbindin-D28k with subsequent impaired renal calcium reabsorption and CsA-induced high turnover bone disease. Additionally, our results suggest that mechanism(s) independent of calbindin-D28k within the kidney also may contribute to the CsA-induced calcium leak.

Animals↗