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PubMed1997

Tau mRNA isoforms following sciatic nerve axotomy with and without regeneration.

The microtubule-associated protein tau promotes the polymerization and stabilization of microtubules in normal neurons and is the main component of paired helical filaments, one of the pathological structures characteristic of Alzheimer's disease (AD). In adult neurons alternative splicing generates tau isoforms with 4 microtubule binding domains (4R tau) while tau in developing neurons contains only 3 such domains (3R tau). The extra microtubule binding domain confers adult tau with an increased ability to interact with and stabilize microtubules. We hypothesized that tau gene expression would revert to the developmental pattern following nerve injury. The sciatic nerve of adult rats was unilaterally crushed or transected and tau mRNA isoform expression in the spinal cord was examined by reverse transcriptase-polymerase chain reaction. At 2 and 3 days post-crush, both the 3R and 4R tau mRNA isoform levels on the injured side had decreased compared to the contralateral side. However, the ratio of 4R to 3R tau mRNA was not significantly different between the two sides at any post-crush time point examined. Following nerve transection, a significant increase in the 3R tau mRNA isoform on the transected compared to the contralateral side occurred at 14 days; the ratio of 4R to 3R tau mRNA was significantly decreased on the transected compared to the contralateral side at 7, 14 and 42 days. These results suggest that a recapitulation of the developmental pattern of 3R tau gene expression occurs following nerve transection but not nerve crush. Our results combined with the recent findings that the 3R tau protein isoform preferentially forms paired helical filament-like structures in vitro suggests that an increased expression of the 3R tau mRNA isoform may also occur in AD.

Aging↗
PubMed1997

Up-regulation of nitric oxide synthase and its mRNA in vagal motor nuclei following axotomy in rat.

Effects of vagotomy on nitric oxide synthase (NOS) protein and mRNA levels in the dorsal motor nucleus of vagus (DMV) and nucleus ambiguus (NA) of rats were examined by nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) staining, brain NOS (bNOS) immunostaining and in situ hybridization. NADPH-d staining and bNOS immunoreactivity increased in neurons of the ipsilateral DMV and NA 5, 10, and 20 days after vagotomy. These changes were not observed in unoperated or sham-operated rats. In situ hybridization showed that bNOS mRNA levels were also elevated in neurons of DMV and NA on the operated side. Our results suggest that transection of vagal efferents up-regulates bNOS and its mRNA expression in the DMV and NA.

Animals↗
PubMed1997

Localization of bradykinin-like immunoreactivity in the rat spinal cord: effects of capsaicin, melittin, dorsal rhizotomy and peripheral axotomy.

A putative role for bradykinin has been proposed in the processing of sensory information at the level of the spinal cord. Autoradiographic studies have demonstrated the presence of B2 kinin receptor binding sites in superficial laminae of the dorsal horn and a down-regulation of those receptors in rat models of pain injury. In this study, classical immunocytochemistry and confocal microscopy immunofluorescence were used first to localize bradykinin-like immunoreactivity in all major spinal cord segments of naive rats; second, to assess bradykinin-like immunoreactivity changes that occur in animals subjected to various chemical treatments and surgical lesions. High densities of bradykinin-like immunoreactivity were observed in motoneuron of the ventral horn, deeper laminae and nucleus dorsalis of the dorsal horn. Higher magnification of ventral horn showed strong immunostaining of motoneuron perikaryas and their proximal processes. Two types of bradykinin-like immunoreactivity immunostained cellular bodies were observed in deeper laminae of the dorsal horn. These interneurons, morphologically corresponding to islets and antenna-type cells project dendrites to adjacent laminae. Furthermore, numerous strongly marked dendrites, transversally cut, suggest the presence of projection neurons to higher cervical centres. Following unilateral lumbar dorsal rhizotomy (L1-L6) or peripheral lesion of the sciatic nerve, important increases of bradykinin-like immunoreactivity were found in laminae III and IV of the ipsilateral dorsal horn. In contrast, significant decreases of immunodeposits were observed in both cell bodies and numerous dendrites of motoneuron surrounding neuropil. Specific destructions of sensory afferent fibres with capsaicin or selective activation of kallikreins with melittin caused increases of bradykinin-like immunoreactivity in both the dorsal and ventral horns of the spinal cord. These results which demonstrate the cellular localization of bradykinin-like immunoreactivity in both dorsal and ventral horns of the rat spinal cord, further reveal the plasticity of this non-sensory peptidergic system following various chemical and surgical treatments. Hence, these anatomical findings along with earlier functional and receptor autoradiographic studies reinforce the putative role of bradykinin in sensory function.

Animals↗
PubMed1997

Axotomy-induced alterations in the red nucleus revealed by monoclonal antibody, Py, following a low thoracic spinal cord lesion in the adult rat.

The monoclonal antibody Py was previously developed as a tool for the identification of subpopulations of hippocampal neurons. Here, the differential distribution of Py immunoreactivity in the mid-brain is described showing that Py also serves as a useful marker for other populations of neurons. Medium to strong immunoreactivity was observed in the cell body and dendrites of neurons of the oculomotor nucleus, superior colliculus and substantia gelatinosa reticulata. However, particularly intense Py-immunoreactivity was identified in the magnocellular neurons in the caudal pole of the red nucleus. Unilateral transection of the rubrospinal tract at Th9-10 induced a marked reduction of Py immunoreactivity in the ventrolateral territory of the caudal pole of the axotomised red nucleus. A small but statistically significant reduction of Py-immunoreactivity was first seen at 7 days after surgery and a maximal loss of immunoreactivity (reduced to 66% of control levels) was observed by 21 days after surgery. Immunoreactivity in the axotomised red nucleus was reduced for the duration of the experiment but at the longer survival times studied (3 and 6 months) a small degrees of recovery of staining was observed in small-medium diameter atrophic neurons. These results indicate that monoclonal antibody Py, may be a useful novel and sensitive tool for investigating the cell body reaction of particular populations of axotomised CNS neurons following spinal cord injury.

Animals↗
PubMed1993

Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve.

The neurotrophin family includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Previous studies have demonstrated that expression of NGF and its low-affinity receptor is induced in nonneuronal cells of the distal segment of the transected sciatic nerve suggesting a role for NGF during axonal regeneration (Johnson, E. M., M. Taniuchi, and P. S. DeStefano. 1988. Trends Neurosci. 11:299-304). To assess the role of the other neurotrophins and the members of the family of Trk signaling neurotrophin receptors, we have here quantified the levels of mRNAs for BDNF, NT-3, and NT-4 as well as mRNAs for trkA, trkB, and trkC at different times after transection of the sciatic nerve in adult rats. A marked increase of BDNF and NT-4 mRNAs in the distal segment of the sciatic nerve was seen 2 wk after the lesion. The increase in BDNF mRNA was mediated by a selective activation of the BDNF exon IV promoter and adrenalectomy attenuated this increase by 50%. NT-3 mRNA, on the other hand, decreased shortly after the transection but returned to control levels 2 wk later. In Schwann cells ensheathing the sciatic nerve, only trkB mRNA encoding truncated TrkB receptors was detected with reduced levels in the distal part of the lesioned nerve. Similar results were seen using a probe that detects all forms of trkC mRNA. In the denervated gastrocnemius muscle, the level of BDNF mRNA increased, NT-3 mRNA did not change, while NT-4 mRNA decreased. In the spinal cord, only small changes were seen in the levels of neutrophin and trk mRNAs. These results show that expression of mRNAs for neurotrophins and their Trk receptors is differentially regulated after a peripheral nerve injury. Based on these results a model is presented for how the different neurotrophins could cooperate to promote regeneration of injured peripheral nerves.

Animals↗
PubMed1995

Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice.

The structure of rat brain-derived neurotrophic factor (BDNF) gene is complex; four 5' exons are linked to separate promoters and one 3' exon is encoding the BDNF protein. To analyze the relative importance of the regulatory regions in vivo, we have generated transgenic mice with six different promoter constructs of the BDNF gene fused to the chloramphenicol acetyl transferase reporter gene. High level and neuronal expression of the reporter gene, that in many respects recapitulated BDNF gene expression, was achieved by using 9 kb of genomic sequences covering the promoter regions that lie adjacent to each other in the genome (promoters I and II and promoters III and IV, respectively) and by including sequences of BDNF intron-exon splice junctions and 3' untranslated region in the constructs. The genomic regions responsible for the in vivo upregulation of BDNF expression in the axotomized sciatic nerve and in the brain after kainic acid-induced seizures and KCl-induced spreading depression were mapped. These data show that regulation of the different aspects of BDNF expression is controlled by different regions in vivo, and they suggest that these promoter constructs may be useful for targeted expression of heterologous genes to specific regions of the central and peripheral nervous systems in an inducible manner.

Animals↗
PubMed1996

HU-211, a nonpsychotropic cannabinoid, produces short- and long-term neuroprotection after optic nerve axotomy.

HU-211 is a novel synthetic analog of tetrahydrocannabinol that was recently shown in animal models to be nonpsychotropic. In this study we show that HU-211 can potentially be used as a neuroprotective compound in the CNS. Using a calibrated crush injury of adult rat optic nerve, we show that HU-211 can reduce injury-induced metabolic and electrophysiological deficits. Energy metabolism was monitored by measuring the intramitochondrial nicotine-amine adenine dinucleotide redox state hourly for 6 h after injury and treatment. Electrophysiological activity was assessed by compound action potential and visual evoked potential response. Beneficial effects were dose-dependent, being optimal at 7 mg/kg, administered intraperitoneally. The time window during which treatment was effective was found to be from the time of injury for at least 5 h, with treatment most effective at the time of injury. These results strongly suggest that HU-211, given immediately after CNS injury at the optimal dosage, may possess neuroprotective activities.

Action Potentials↗
PubMed1992

Induction of c-jun expression in vagal motoneurones following axotomy.

Using in situ hybridization, we have measured c-jun mRNA expression in the caudal medulla oblongata of the rat following sectioning of the cervical vagus nerve. Twenty four hours after either unilateral cervical vagotomy or nodose ganglionectomy, motoneurones in the ipsilateral dorsal motor nucleus of the vagus and nucleus ambiguus expressed increased (2-3 fold) levels of c-jun mRNA. After 7 days, c-jun mRNA expression was further elevated to levels 8-10-fold higher than basal. These results demonstrate an unusual, long-lasting activation of a member of the 'leucine zipper' class of immediate early gene, and suggest that immediate early genes such as c-jun may be responsible for the regulation of the expression of structural protein and neuropeptide genes that have been demonstrated to occur following nerve injury.

Animals↗
PubMed1996

Evidence for galanin receptors in primary sensory neurones and effect of axotomy and inflammation.

Using in situ hybridization, mRNA coding for the galanin R1 receptor (GAL-R1) was demonstrated in > 20% of all lumbar 4 and 5 dorsal root ganglion neurone profiles, mainly constituting small and medium sized neurones. Almost all of these neurones expressed CGRP mRNA as revealed by analysis of adjacent sections and of the same section using a double-labelling technique. GAL-R1 mRNA levels were down-regulated transiently by inflammation, and more strongly by peripheral nerve injury. These results suggest that DRG neurones are sensitive to galanin and that GAL-R1 receptors are involved in sensory processing.

Animals↗
PubMed1997

Downregulation of metabotropic glutamate receptor 1a in motoneurons after axotomy.

Axotomized motoneurons display drastic modifications in synaptic structure and function related to their disconnection from the periphery and establishment of a regenerative metabolic functional mode. The molecular basis of these modifications is not fully understood. Here we describe changes in metabotropic glutamate receptor 1a (mGluR1a)-immunoreactivity 3, 7 or 14 days after unilateral aciatic transection. mGluR1a-immunoreactivity was distributed throughout the somatic cytoplasm and somatodendritic membrane of uninjured motoneurons and was significantly reduced in axotomized motoneurons. This reduction was observed at 3 days and grew progressively over 2 weeks. These findings suggest that downregulation of mGluR1a could contribute to reduced excitatory neurotransmission in axotomized motoneurons.

Animals↗
PubMed1977

H3T-labelled blood cells in the CNS response to axotomies at various times after isotope injection.

Numerous investigators, using tritiated thymidine to label mononuclear blood cells, have proposed a hematogenous origin for some of the reactive cells responding to injury in the CNS. However, two questions have remained unanswered: recirculation of H3T at the time of injury with labelling of proliferating local cells; and local reutilization of label released from degenerating cells. In a recently reported experiment using bilateral injuries made at different times (24), a large number os labelled cells responding to the second injury resulted from mitosis of cells already reacting to injury on the contralateral side. Additionally, the possibility that some of the labelled cells could have been newly drived from blood was not ruled out. The present experiment was designed to further explore this possibility. To minimize the problems of H3T recirculation and reutilization, the isotope was injected 3 to 17 days before nerve injury in some of the animals. At sacrifice, labelled cells were found in the nucleus of the injured nerve up to 36 days after isotope injection, with the peak of the reaction occurring at 9 days. Since the isotope was injected 3 to 17 days before injury and because there was no source of reactive cells on the contralateral side, it was felt that these labelled cells were newly derived from blood.

Animals↗