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B J Hoffer

Publications and source records attributed to B J Hoffer.

At least 19 recordsLinked to original sources
PubMed2006

A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Levels of GDNF deteriorate in the substantia nigra in Parkinson's disease (PD). A heterozygous mouse model was created to assess whether chronic reductions in this neurotrophic factor impact motor function and the nigrostriatal dopamine system during the aging process. Due to the important role GDNF plays in kidney development, kidney function and histology were assessed and were found to be normal in both wild-type (WT) and GDNF+/- mice up to 22 months of age. Further, the animals of both genotypes had similar weights throughout the experiment. Locomotor activity was assessed for male WT and GDNF+/- mice at 4-month intervals from 4 to 20 months of age. Both GDNF+/- and WT mice exhibited an age-related decline in horizontal activity, although this was found 4 months earlier in GDNF+/- mice, at 12 months of age. Comparison of young (8 month old) and aged (20 month old) GDNF+/- and WT mice on an accelerating rotarod apparatus established a deficiency for aged but not young GDNF+/- mice, while aged WT mice performed as well as young WT mice on this task. Finally, both WT and GDNF+/- mice exhibited an age-related decrease in substantia nigra TH immunostaining, which was accelerated in the GDNF+/- mice. These behavioral and histological alterations suggest that GDNF may be an important factor for maintenance of motor coordination and spontaneous activity as well as DA neuronal function during aging, and further suggest that GDNF+/- mice may serve as a model for neuroprotective or rescue studies.

Age Factors↗
PubMed2004

Neurotrophic effects of bone morphogenetic protein-7 in a rat model of Parkinson's disease.

Previous studies have demonstrated that pretreatment with bone morphogenetic protein-7 (BMP7) reduces ischemic neuronal injury in vivo. Moreover, exogenous application of BMP7 increases both the number of tyrosine hydroxylase (+) cells and dopamine (DA) uptake in rat mesencephalic cell cultures. The purpose of this study was to investigate the in vivo effects of BMP7 on 6-hydroxydopamine (6-OHDA) induced lesioning of midbrain DA neurons. Adult Fischer 344 rats were anesthetized and injected with BMP7 or vehicle into the left substantia nigra, followed by local administration of 9 microg of 6-OHDA into the left medial forebrain bundle. The lesioned animals that received BMP7 pretreatment, as compared to vehicle/6-OHDA controls, had a significant reduction in methamphetamine-induced rotation 1 month after the surgery. BMP7-pretreatment partially preserved KCl-induced dopamine release in the lesioned striatum and significantly increased TH immunoreactivity in the lesioned nigra and striatum. In summary, our data suggest that BMP7 has neuroprotective and/or neuroreparative effects against 6-OHDA lesioning of the nigrostriatal DA pathway in an animal model of Parkinson's disease (PD).

Adrenergic Agents↗
PubMed2004

Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus-hippocampal noradrenergic pathway.

It has been shown that the noradrenergic (NE) locus coeruleus (LC)-hippocampal pathway plays an important role in learning and memory processing, and that the development of this transmitter pathway is influenced by neurotrophic factors. Although some of these factors have been discovered, the regulatory mechanisms for this developmental event have not been fully elucidated. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor influencing LC-NE neurons. We have utilized a GDNF knockout animal model to explore its function on the LC-NE transmitter system during development, particularly with respect to target innervation. By transplanting various combinations of brainstem (including LC) and hippocampal tissues from wildtype or GDNF knockout fetuses into the brains of adult wildtype mice, we demonstrate that normal postnatal development of brainstem LC-NE neurons is disrupted as a result of the GDNF null mutation. Tyrosine hydroxylase immunohistochemistry revealed that brainstem grafts had markedly reduced number and size of LC neurons in transplants from knockout fetuses. NE fiber innervation into the hippocampal co-transplant from an adjacent brainstem graft was also influenced by the presence of GDNF, with a significantly more robust innervation observed in transplants from wildtype fetuses. The most successful LC/hippocampal co-grafts were generated from fetuses expressing the wildtype GDNF background, whereas the most severely affected transplants were derived from double transplants from null-mutated fetuses. Our data suggest that development of the NE LC-hippocampal pathway is dependent on the presence of GDNF, most likely through a target-derived neurotrophic function.

Animals↗
PubMed2003

Differential expression of the cell line-derived neurotrophic factor (GDNF) receptor GFRalpha1 in heterozygous Gfralpha1 null-mutant mice after stroke.

Exogenous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-induced cerebral infarction. Cerebral ischemia induces gene expression of GDNF, GDNF-receptor alpha-1 (GFRalpha-1) and c-Ret, suggesting that a GDNF signaling cascade mechanism may be involved in endogenous neuroprotection during ischemia. In the present study, we examined if this endogenous neuroprotective pathway was altered in Gfralpha-1 deficient mice. Since mice homozygous for the Gfralpha-1 deletion (-/-) die within 24 h of birth, stroke-induced changes in the levels of Gfralpha-1 mRNA were studied in Gfralpha-1 heterozygous (+/-) mice and their wild-type (+/+) littermates. The right middle cerebral artery was transiently ligated for 45 min in anesthetized mice. Animals were killed at 0, 6, 12 and 24 h after the onset of reperfusion and levels of Gfralpha-1 mRNA were measured by in situ hybridization histochemistry. Previously, we showed that Gfralpha-1 (+/-) mice are more vulnerable to focal cerebral ischemia. In the present study, we found that basal levels of GFRalpha-1 mRNA were at similar low levels in cortex and striatum in adult Gfralpha-1 (+/+) and Gfralpha-1 (+/-) mice and that ischemia/reperfusion induced up-regulation of Gfralpha-1 mRNA in the lesioned and contralateral sides of cortex and striatum in both Gfralpha-1 (+/+) and GFRalpha-1 (+/-) mice. However, the ischemia/reperfusion induction of Gfralpha-1 mRNA was significantly higher in the cortex of wild type mice, as compared to Gfralpha-1 (+/-) mice. Moreover, the increased expression of Gfralpha-1 in striatum after reperfusion occurred earlier in the GFRalpha-1 (+/+) than in the Gfralpha-1 (+/-) mice. These results indicate that after ischemia, there is a differential up-regulation of Gfralpha-1 expression in Gfralpha-1 (+/+) and Gfralpha-1 (+/-) mice. Since GDNF has neuroprotective effects, the reduced up-regulation of Gfralpha-1 in Gfralpha-1 (+/-) mice at early time points after ischemia suggests that the responsiveness to GDNF and GDNF receptor mediated neuroprotection is attenuated in these genetically modified animals and may underlie their greater vulnerability.

Animals↗
PubMed2003

HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury.

Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary cortical cultures HSVgdnf reduced oxidant-induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex 4 days prior to, or 3 days, after a 60-min unilateral occlusion of the middle cerebral artery. Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed 1 month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein and the apoptotic marker caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS.

Animals↗
PubMed2003

Glial cell line neurotrophic factor-family receptor alpha-1 is present in central neurons with distinct phenotypes.

Glial cell line neurotrophic factor(GDNF) is a potent survival factor for several types of neurons. GDNF binds with high affinity to the GDNF-family receptor alpha-1 (GFRalpha-1) which is expressed in different brain areas. In the present study, by using anatomical techniques, we document the phenotypic diversity among GFRalpha-1 expressing neurons in the CNS. GFRalpha-1 expression was found in GABA (gamma-aminobutyric acid)-containing neurons distributed in the cortex, reticular thalamic nucleus and septum. While high expression of GFRalpha-1 was often observed in cholinergic motoneurons in the spinal cord, very few septal cholinergic neurons were found to express GFRalpha-1. GFRalpha-1 transcripts were also detected in catecholaminergic neurons in the periventricular hypothalamic nucleus, dorsal raphe nucleus and locus ceruleus. Within the raphe nucleus, GFRalpha-1 expression was prominent in many serotonergic neurons and in few neurons containing the enzyme nitric oxide synthase. As GFRalpha-1 is activated by GDNF and GDNF-related neurotrophic factors, the widespread distribution of GFRalpha-1 in neurons with different phenotypes indicates that the neuronal activity of these neurons is likely to be affected by GDNF and GDNF-related neurotrophic factors. This would result in the regulation of diverse neuronal pathways in the adult brain. Published by Elsevier Science Ltd on behalf of IBRO.

Acetylcholine↗
PubMed2003

The noradrenergic system of aged GDNF heterozygous mice.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for noradrenergic (NE) neurons of the pontine nucleus locus coeruleus (LC). Decreased function of the LC-NE neurons has been found during normal aging and in neurodegenerative disorders. We have previously shown that GDNF participates in the differentiation of LC-NE neurons during development. However, the continued role of GDNF for LC-NE neurons during maturation and aging has not been addressed. We examined alterations in aged mice that were heterozygous for the GDNF gene (Gdnf+/-). Wild-type (Gdnf+/+) and Gdnf+/- mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis. Spontaneous locomotion was reduced in Gdnf+/- mice in comparison with Gdnf+/+ mice. The reduced locomotor activity of Gdnf+/- mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC. Tyrosine hydroxylase (TH) immunostaining demonstrated morphological alterations of LC-NE cell bodies and abnormal TH-positive fibers in the hippocampus, cerebellum, and frontal cortex of Gdnf+/- mice. These findings suggest that the LC-NE system of Gdnf+/- mice is impaired and suggest that GDNF plays an important role in continued maintenance of this neuronal system throughout life.

Aging↗
PubMed2001

GFRalpha-1 mRNA in dopaminergic and nondopaminergic neurons in the substantia nigra and ventral tegmental area.

Glial cell line-derived neurotrophic factor (GDNF) is a survival factor for several types of neurons, including dopaminergic (DAergic) neurons. GDNF binds with high affinity to the GDNF family receptor alpha-1 (GFRalpha-1), which is highly expressed in the midbrain. Using anatomical and lesion techniques, we demonstrated that GFRalpha-1 was expressed in DAergic and non-DAergic neurons in the rat midbrain. Immunohistochemical characterization of GFRalpha-1-expressing neurons indicated that most of the neurons that were immunopositive for the DAergic marker tyrosine hydroxylase (TH) expressed GFRalpha-1 in the substantia nigra pars compacta (SNC). In contrast, fewer TH-containing neurons expressed GFRalpha-1 in the substantia nigra pars reticulata (SNR) and the ventral tegmental area (VTA). Depletion of GFRalpha-1/TH neurons was observed in the SNC following treatment with the neurotoxin 6-hydroxydopamine (6-OHDA); however, GFRalpha-1 expression remained in some neurons located in the SNR. The gamma-aminobutyric acid (GABA)ergic nature of GFRalpha-1-expressing neurons located in the SNR, which were resistant to (6-hydroxydopamine) 6-OHDA, was established by their expression of glutamic acid decarboxylase (GAD; the synthesizing enzyme for GABA). Further analysis indicated that coexpression of GFRalpha-1 and GAD varied in a rostrocaudal gradient in the SNR, substantia nigra pars lateralis (SNL), and VTA. Midbrain DAergic and GABAergic neurons have been previously classified according to their Ca(2+) binding protein (CaBP) content; thus, we also sought to investigate the proportion of midbrain GFRalpha-1-expressing neurons containing parvalbumin (PV), calbindin (CB), and calretinin (CR) in the midbrain. Although GFRalpha-1 expression was found mainly in CB- and CR-immunoreactive neurons, it was rarely observed in PV-immunolabeled neurons. Analysis of the proportion of GFRalpha-1-expressing neurons for each CaBP subpopulation indicated the coexistence of GFRalpha-1 with CR in the VTA and all subdivisions of the SN; double-labeled GFRalpha-1/CR neurons were distributed in the SNC, SNR, SNL, and VTA. GFRalpha-1/CB neurons were also detected in the SNC, SNL, and VTA. Expression of GFRalpha-1 in DAergic and non-DAergic neurons in the rat SN and VTA suggests that GDNF, via GFRalpha-1, might modulate DAergic and GABAergic functions in the nigrostriatal, mesolimbic, and nigrothalamic circuits of the adult rat.

Animals↗
PubMed2001

Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.

Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.

Animals↗
PubMed2001

Cellular mRNA expression of the transcription factor NGFI-B suggests a gene regulatory role in striatal opiate-peptide neurons.

Previous studies have shown that NGFI-B mRNA is highly expressed in the adult striatum. In the present study we analyzed the anatomical distribution of NGFI-B mRNA within this brain region as well as the degree of co-existence of NGFI-B with different striatal markers in the adult brain. NGFI-B mRNA levels were found to be significantly higher within the dorsomedial portion of the striatum as compared to the ventrolateral striatum. This distribution pattern was maintained throughout the rostro--caudal axis of the striatum. Double in situ hybridization studies showed that striatal NGFI-B mRNA colocalized with a subset of preproenkephalin and prodynorphin positive spiny neurons within the dorsomedial striatum; 22--28% of all opiate-peptide positive cells co-expressed NGFI-B mRNA. NGFI-B did not colocalize with striatal aspiny interneurons expressing choline acetyl transferase mRNA or those containing the calcium-binding protein parvalbumin. The pattern of NGFI-B mRNA expression within different striatal spiny projecting neurons suggests that this transcription factor may have a direct effect on the function of different striatal efferent pathways.

Animals↗
PubMed2001

Fetal intra-nigral ventral mesencephalon and kidney tissue bridge transplantation restores the nigrostriatal dopamine pathway in hemi-parkinsonian rats.

We have previously demonstrated that intranigral transplantation of fetal ventral mesencephalic (VM) tissue and nigrostriatal administration of glial cell line-derived neurotrophic factor (GDNF) restores striatal dopamine input in hemiparkinsonian rats. Since it has been found that GDNF is highly expressed in fetal kidney, we examined the possibility that fetal kidney tissue may provide trophic support, similar to GDNF, to an intranigral dopamine (DA) transplant and restore the nigrostriatal pathway. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Completeness of the lesion was evaluated by measuring amphetamine-induced rotation. One month after 6-OHDA lesioning, fetal VM cells were grafted into the lesioned nigral area followed by transplantation of fetal kidney tissue or vehicle along a pathway from nigra to striatum. Animals receiving these transplants showed a significant decrease both in amphetamine-induced rotation and in postural asymmetry 1 to 3 months after grafting. Immunocytochemical studies demonstrated tyrosine hydroxylase (TH) positive fiber tracts in the lesioned striatum. Control animals that received vehicle injection after the intranigral graft or no transplantation showed no alterations in amphetamine-induced turning and no TH-positive fibers in the lesioned striatum. These results indicate that combinations of fetal nigral and kidney transplants may restore the nigrostriatal DA pathway in Parkinsonian rats. As fetal kidney contains a variety of trophic proteins, it may provide a synergistic admixture to optimally promote DA fiber outgrowth.

Amphetamine↗
PubMed2001

Expression of neural cell adhesion molecule in spinal cords following a complete transection.

Neural cell adhesion molecule (NCAM) regulates tissue organization during development and in the adult. NCAM upregulation occurs after an injury to brains and sciatic nerves. However, little is known about NCAM expression after spinal cord injury (SCI). By using a complete spinal cord transection with a 5 mm tissue removal, an increase in the NCAM level is detected in spinal cord stumps proximal and distal to the transection site at 1 d and 3 d post injury, while its expression at 8 d is declined to a lower level than that observed in sham-operated spinal cords. The strong NCAM expression is present in motor neurons at 3 d post transection whereas the intensive NCAM immunostaining is localized in dorsal sensory and corticospinal fiber tracts at 8 d following injury. Collectively, NCAM level is elevated and strongly expressed in dorsal fiber tracts after SCI, implying that the endogenous process for spinal cord regeneration may take place after SCI.

Animals↗
PubMed2001

Time course study of GFRalpha-1 expression in an animal model of stroke.

Previous studies have shown that intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-mediated cerebral infarction. The biological effects of GDNF are mediated by GDNF-family receptor alpha-1 (GFRalpha-1) and c-Ret. In this study, we examined the levels of expression of GFRalpha-1 and c-Ret in a rat model of stroke. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The right middle cerebral artery was ligated at its distal branch for 90 min. Animals were sacrificed at 0, 6, 12, and 24 h after reperfusion and levels of expression of GFRalpha-1 and c-Ret mRNA were determined by in situ hybridization histochemistry. We found that GFRalpha-1 mRNA was up-regulated in CA3, dentate gyrus (DG), cortex, and striatum. The peak of up-regulation in DG was 6 h after reperfusion. GFRalpha-1 mRNA levels in CA3 were gradually up-regulated over the 24-h reperfusion period. In cortex, GFRalpha-1 mRNA was up-regulated at all time points; however, the peak of up-regulation was observed at 0 and 24 h after reperfusion. In striatum, an initial up-regulation of GFRalpha-1 was found at 0 h after ischemia. In striatum, up-regulation of c-Ret mRNA was detected as early as 0 h after reperfusion. A gradual increase was found at 6, 12, and 24 h after reperfusion. In conclusion, our results indicate that there are both regional and temporal differences in up-regulation of GFRalpha-1 and c-Ret after ischemia. Since GDNF is neuroprotective, up-regulation of GFRalpha-1 and c-Ret could enhance the responsiveness to GDNF and reduce neuronal damage. The selective up-regulation of GFRalpha-1 and c-Ret in different brain areas suggests that there may be regional differences in GDNF-induced neuroprotection in stroke.

Analysis of Variance↗
PubMed2001

In vivo extracellular recording of striatal neurons in the awake rat following unilateral 6-hydroxydopamine lesions.

The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving animal; this model should prove useful for testing the behavioral and functional effects of experimental manipulations designed to reduce or reverse the effects of dopaminergic cell loss. In addition, these results suggest that the contralateral changes in striatal function which occur in the unilateral dopaminergic lesion model should be considered when evaluating experimental results.

Action Potentials↗
PubMed2001

Involvement of GDNF in neuronal protection against 6-OHDA-induced parkinsonism following intracerebral transplantation of fetal kidney tissues in adult rats.

Exogenous application of transforming growth factors-beta (TGF beta) family proteins, including glial cell line-derived neurotrophic factor (GDNF), neurturin, activin, and bone morphogenetic proteins, has been shown to protect neurons in many models of neurological disorders. Finding a tissue source containing a variety of these proteins may promote optimal beneficial effects for treatment of neurodegenerative diseases. Because fetal kidneys express many TGF beta trophic factors, we transplanted these tissues directly into the substantia nigra after a unilateral 6-hydroxydopamine lesion. We found that animals that received fetal kidney tissue grafts exhibited (1) significantly reduced hemiparkinsonian asymmetrical behaviors, (2) a near normal tyrosine hydroxylase immunoreactivity in the lesioned nigra and striatum, (3) a preservation of K(+)-induced dopamine release in the lesioned striatum, and (4) high levels of GDNF protein within the grafts. In contrast, lesioned animals that received grafts of adult kidney tissues displayed significant behavioral deficits, dopaminergic depletion, reduced K(+)-mediated striatal dopamine release, and low levels of GDNF protein within the grafts. The present study suggests that fetal kidney tissue grafts can protect the nigrostriatal dopaminergic system against a neurotoxin-induced parkinsonism, possibly through the synergistic release of GDNF and several other neurotrophic factors.

Age Factors↗
PubMed2001

Bone morphogenetic protein-6 reduces ischemia-induced brain damage in rats.

BACKGROUND AND PURPOSE: Bone morphogenetic protein-6 (BMP6) and its receptors are expressed in adult and fetal brain. Receptors for BMP6 are upregulated in adult brain after injury, leading to the suggestion that BMP6 is involved in the physiological response to neuronal injury. The purpose of this study was to determine whether there was a neuroprotective effect of BMP6 in vivo and in vitro. METHODS: Lactate dehydrogenase and microtubule-associated protein-2 (MAP-2) activities were used to determine the protective effect of BMP6 against H(2)O(2) in primary cortical cultures. The neuroprotective effects of BMP6 were also studied in chloral hydrate-anesthetized rats. BMP6 or vehicle was injected into right cerebral cortex before transient right middle cerebral artery (MCA) ligation. Animals were killed for triphenyl-tetrazolium chloride staining, caspase-3 immunoreactivity and enzymatic assays, and TUNEL assay. A subgroup of animals were used for locomotor behavioral assays. RESULTS: Application of H(2)O(2) increased lactate dehydrogenase activity and decreased the density of MAP-2(+) neurons in culture. Both responses were attenuated by BMP6 pretreatment. Complementary in vivo studies showed that pretreatment with BMP6 increased motor performance and generated less cerebral infarction induced by MCA ligation/reperfusion in rats. Pretreatment with BMP6 did not alter cerebral blood flow or physiological parameters. There was decreased ischemia-induced caspase-3 immunoreactivity, caspase-3 enzymatic activity, and density of TUNEL-positive cells in ischemic cortex in BMP6-treated animals. CONCLUSIONS: BMP6 reduces ischemia/reperfusion injury, perhaps by attenuating molecular events underlying apoptosis.

Animals↗
PubMed2000

GFR alpha-1 is expressed in parvalbumin GABAergic neurons in the hippocampus.

Glial cell line derived neurotrophic factor (GDNF) is a potent survival factor for several types of neurons. GDNF binds with high affinity to GDNF-family receptor alpha-1 (GFR alpha-1). This receptor is expressed in different areas of the brain, including the hippocampus and dentate gyrus. By using in situ hybridization and immunohistochemistry, we found that 19% to 37% of glutamic acid decarboxylase (GAD) expressing neurons co-expressed GFR alpha-1 in the hippocampus. GFR alpha-1/GAD co-expression was found mainly in the stratum (s) pyramidale (29-37%) and s. oriens (20-25%). Further characterization of GFR alpha-1 expressing interneurons, based on their calcium-binding protein immunoreactivity, demonstrated that many parvalbumin (PV) immunoreactive neurons express GFR alpha-1 in the s. pyramidale of CA1 (72%), CA2 (70%) and CA3 (70%) subfields of the hippocampus. GFR alpha-1/PV double labeled neurons were also detected in the s. oriens of CA1 (52%), CA2 (27%) and CA3 (36%) subfields. The expression of GFR alpha-1 in principal neurons and in a specific sub-population of GABAergic neurons (PV-containing neurons) suggest that GDNF might modulate, in a selective manner, functions of the entire adult hippocampus.

Animals↗