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PubMed1998

Effect of inferior alveolar nerve axotomy on periodontal and pulpal blood flow subsequent to experimental tooth movement in rats.

The aims of this study were to evaluate the effect of inferior alveolar nerve (IAN) axotomy on periodontal (PDL) and pulpal blood flow incident to experimental tooth movement and to investigate whether nerve fiber regeneration coincides with blood flow changes. The first right mandibular molar was moved mesially for 3, 7, and 14 days after ipsilateral IAN axotomy in 29 rats. Four rats served as unoperated controls. At the end of each experimental period fluorescent microspheres (FM) were injected into the left ventricle and thereafter counted in serial sections in the PDL and pulp of the right and left first mandibular molars. The number of FM per tissue volume was taken as a measure of blood flow. Re-innervation of nerve fibers was mapped immunohistochemically 7, 14, and 21 days after IAN axotomy in 9 rats that had no orthodontic appliance. The statistical analysis showed no significant differences in the number of FM/mm3 PDL between the denervated and the contralateral side at 3 and 7 days. At 14 days the PDL on the denervated side showed a significant increase in the number of FM/mm3, coinciding with the initial periodontal nerve fiber re-innervation. In the pulp no significant differences were found between the denervated and the contralateral, innervated side in any experimental period. It can be concluded that IAN axotomy postpones an increase in periodontal blood flow until a sensory tissue re-innervation is established, thus indicating that neurogenic mechanisms play an important role in the development of the inflammatory reaction induced by experimental tooth movement.

Animals↗
PubMed2003

Apoptosis onset and bax protein distribution in spinal motoneurons of newborn rats following sciatic nerve axotomy.

Extensive apoptosis in spinal cord motoneuron was reported to occur in the newborn following sciatic nerve axotomy. The purpose of this study was to evaluate the onset of cell death at early stages of axotomy, and the changes in Bax protein distribution pattern in the apoptotic cell. Newborn rats were divided into seven groups, axotomized at day 5 postnatal and sacrificed at the following time points: 1, 3, 6, 12, 24, 48, and 72 h after surgery. The left sciatic nerve was transected while the right side was kept as a control. Three experiments were made for morphometric, immunohistochemical, and ultrastructural studies. Morphometric study showed sustained reduction in the number of neurons in the ventral horn. Neuronal losses onset occurred at the first hour after axotomy and the highest loss occurred in the 72-h group (33.7%). The percentage of survived motoneuron (PSM) was calculated. The test of linearity showed that neuron reduction pattern was nonlinear. A nonlinear curve fitting of PSM against time showed an exponential decline in the number of neurons. Immunohistochemistry results showed three Bax protein patterns; early stage increase in Bax gene expression; Bax protein punctation; and dense Bax protein immunoreactivity (DBI). The last two can either be early or late patterns. Bax gene expression increased as early as the first hour post-axotomy and the number of Bax-positive motoneurons continued to increase throughout the time course. Ultrastructural study of the cytoplasm showed an early vacuolation in Golgi apparatus and endoplasmic reticulum that was associated by mitochondrial and nuclear changes.

Animals↗
PubMed2005

Fibroblast growth factor 2 applied to the optic nerve after axotomy increases Bcl-2 and decreases Bax in ganglion cells by activating the extracellular signal-regulated kinase signaling pathway.

We have shown that application of basic fibroblast growth factor (FGF-2) to axotomized optic nerve promotes the survival of frog retinal ganglion cells (RGCs). In the present study we used western blotting and immunocytochemistry to investigate the effects of this FGF-2 treatment upon the activation of the extracellular signal-regulated kinase (ERK) pathway, the amounts and distribution of Bcl-2 family proteins, and the activation of caspase-3. Axotomy alone temporarily increased ERK activation; FGF-2 treatment to the nerve prolonged this activation. This effect was blocked by U0126, a selective ERK kinase (MEK) inhibitor. Axotomy caused a decrease in Bcl-2 and a small increase in Bcl-x(L). FGF-2 treatment caused an ERK-dependent increase in Bcl-2 and an ERK-independent increase in Bcl-x(L). The pro-apoptotic Bax was increased by axotomy; FGF-2 treatment greatly decreased Bax levels, an effect that was inhibited by U0126. Axotomy induced the cleavage of caspase-3; FGF-2 treatment blocked this effect in an ERK-dependent manner. Finally, intraocular application of the MEK inhibitor caused a large reduction in the survival-promoting effect that FGF-2 application to the nerve stump had on RGCs. Our results suggest that FGF-2 acts, at least in part, via the ERK pathway to prevent apoptosis of axotomized RGCs not only by increasing amounts of anti-apoptotic proteins, but also by a striking reduction in the levels of apoptotic effectors themselves.

Animals↗
PubMed2005

JNK inhibitory kinase is up-regulated in retinal ganglion cells after axotomy and enhances BimEL expression level in neuronal cells.

Optic nerve transection results in retinal ganglion cell (RGC) death in adult mammals, after the alteration of gene expression of RGCs. To elucidate the molecular mechanism by which axotomy induces RGC death, we isolated the molecules up-regulated after optic nerve transection. One of these, axotomy-related [corrected] gene (ARG)357, an 898-amino-acid [corrected] protein containing a complete serine-threonine kinase domain, was isolated from a subtraction library of the rat retina. The sequence showed that this gene was a rat homolog of human c-Jun N-terminal kinase (JNK) inhibitory kinase and so belonged to the germinal center kinase-VIII subfamily of Sterile20s protein kinase. We designated ARG357 as rat JNK inhibitory kinase (JIK). Rat JIK was expressed ubiquitously in various tissues and was highly expressed in the retina, with selective expression in RGCs. After axotomy, BimEL and Hrk, which are BH3-only proteins, and rat JIK were up-regulated in RGCs. Overexpression of rat JIK in neuronal cells up-regulated the expression of BimEL, but not that of Hrk. These results indicate that JIK may contribute to axotomy-induced RGC death by up-regulating the expression of BH3-only protein.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Regulation of axotomy-induced dopaminergic neuron death and c-Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase.

Mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB) results in the delayed degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We have previously demonstrated that c-Jun activation is an obligate component of neuronal death in this model. Here we identified the small GTPase, cdc42, and mixed lineage kinases (MLKs) as upstream factors regulating neuronal loss and activation of c-Jun following MFB axotomy. Adenovirus-mediated expression of a dominant-negative form of cdc42 in nigral neurons blocked MFB axotomy-induced activation (phosphorylation) of MAP kinase kinase 4 (MKK4) and c-Jun, resulting in attenuation of SNpc neuronal death. Pharmacological inhibition of MLKs, MKK4-activating kinases, significantly reduced the phosphorylation of c-Jun and abrogated dopaminergic neuronal degeneration following MFB axotomy. Taken together, these findings suggest that death of nigral dopaminergic neurons following axotomy can be attenuated by targeting cell signaling events upstream of c-Jun N-terminal mitogen-activated protein kinase/c-Jun.

Animals↗
PubMed2002

Reduced NR2A expression and prolonged decay of NMDA receptor-mediated synaptic current in rat vagal motoneurons following axotomy.

To elucidate characteristic changes in the N-methyl-D-aspartate (NMDA) receptor on neurons following axotomy, subunit expressions and functional features of the NMDA receptor were examined in the dorsal motor nucleus of vagus (DMV) of rats receiving vagal axotomy at the neck. Western blotting analysis demonstrated that the expression of NR2A decreased 2-3 days after in vivo axotomy, while expression of NR1 and NR2B, NR2C and NR2D subunits did not change significantly. To examine the functional changes, patch clamp recordings in whole-cell mode were employed on the axotomized DMV neurons identified by retrograde labelling with fluorescent dye. The amplitude ratios of ifenprodil-sensitive components of NMDA response and D,L-2-amino-5-phosphovaleric acid (APV)-sensitive evoked postsynaptic current increased after axotomy. In addition, APV-sensitive postsynaptic currents exhibited a longer decay time in identified axotomized vagal motoneurons than in control neurons. No significant differences in the current density of the NMDA response and the peak amplitude of APV-sensitive synaptic currents were observed between axotomized and intact DMV neurons. In conclusion, a decrease in NR2A expression results in the appearance of functional characteristics of the NMDA receptor predominantly containing the NR2B subunit. This might lead to a long-term increase of the susceptibility of neurons to excitotoxicity.

Animals↗
PubMed2004

Neural activity protects hypothalamic magnocellular neurons against axotomy-induced programmed cell death.

Axotomy typically leads to retrograde neuronal degeneration in the CNS. Studies in the hypothalamo-neurohypophysial system (HNS) have suggested that neural activity is supportive of magnocellular neuronal (MCN) survival after axotomy. In this study, we directly test this hypothesis by inhibiting neural activity in the HNS, both in vivo and in vitro, by the use of tetrodotoxin (TTX). After median eminence compression to produce axonal injury, unilateral superfusion of 3 microM TTX into the rat supraoptic nucleus (SON), delivered with the use of a miniature osmotic pump for 2 weeks in vivo, produced a decrease in the number of surviving MCNs in the TTX-treated SON, compared with the contralateral untreated side of the SON. In vitro application of 2.5 microM TTX for 2 weeks to the SON in organotypic culture produced a 73% decrease in the surviving MCNs, compared with untreated control cultures. Raising the extracellular KCl in the culture medium to 25 mM rescued the MCNs from the axotomy- and TTX-induced cell death. These data support the proposal that after axotomy, neural activity is neuroprotective in the HNS.

Animals↗
PubMed2002

Identification of an axotomy-induced glycosylated protein, AIGP1, possibly involved in cell death triggered by endoplasmic reticulum-Golgi stress.

We developed a new method, designated N-linked glycosylation signal (NGS) differential display (DD)-PCR, that enables the identification of genes encoding N-linked glycosylated molecules that exhibit varying patterns of expression. Using this innovative technique, we identified an N-linked glycosylated 11-transmembrane domain protein that is upregulated in response to axotomy. Expression levels increased 3 d after axotomy, reached maximal levels at approximately postoperative days 5-7, and then gradually decreased through day 20. The protein was termed axotomy-induced glycosylated/Golgi-complex protein 1 (AIGP1). AIGP1 immunoreactivity is specifically localized in neurons, with subcellular localization within the Golgi, indicating that AIGP1 is a resident Golgi protein. Moreover, AIGP1 gene expression in cultured neurons is specifically induced by the endoplasmic reticulum (ER)-Golgi stressors tunicamycin and brefeldin A. We observed that the frequency of cell death is increased by AIGP1 overexpression and that the corresponding region of the protein implicated in the activity involves the large eighth and ninth transmembrane loops. Our results suggest that AIGP1 gene activation and protein accumulation in the Golgi complex in response to axotomy-induced ER-Golgi stress may contribute to signaling during programmed cell death in damaged neurons.

Animals↗
PubMed2003

Regeneration of ganglion cell axons into a peripheral nerve graft alters retinal expression of glial markers and decreases vulnerability to re-axotomy.

PURPOSE: To compare the effect of cutting the optic nerve versus replacing the cut optic nerve with a peripheral nerve (PN) graft on retinal glial markers, and to determine whether the PN graft can stabilize regenerating retinal ganglion cells (RGCs), thus preventing their death following re-axotomy. METHODS: Retinas harvested after ganglion cell regeneration into a sciatic nerve graft were compared to untreated control retinas and retinas obtained following optic nerve axotomy. Glial-specific proteins such as glial fibrillary acidic protein (GFAP), Bcl-2 and complement-3 receptor (Ox-42) were examined using immunohistochemistry. Ganglion cells that survived the second axotomy were quantified on retinal flat mounts by retrograde labeling from the graft. RESULTS: GFAP expression in astrocytes and Muller cells was elevated in axotomized retinas when compared to controls, and an additional up-regulation in Muller cells was found in retinas following ganglion cell regeneration. Increased GFAP expression in retinas containing regenerated neurons was accompanied by increased Bcl-2 expression with latter being confined to Muller cells. Moreover, re-axotomy of the regenerated axons within the graft did not result in significant retrograde degeneration of RGCs within 28 days. CONCLUSIONS: The data suggest that the graft stabilizes the regenerating RGCs to an extent reminiscent of peripheral neurons, a process that may involve the interaction between neuronal and glial elements.

Animals↗
PubMed2003

[Protective effect of exogenous bcl-2 on spinal cord motoneurons following sciatic nerve axotomy in the rat].

The aim of this study was to investigate the protective effect of exogenous bcl-2 on spinal cord motoneurons following sciatic nerve axotomy. After epineurium suturing, sense bcl-2 (Ad/s-bcl-2), antisense bcl-2 (Ad/as-bcl-2), or reporter gene lacZ (Ad/lacZ) recombinant adenovirus or NS was injected into the sciatic nerve 0.5 cm distant from the sutured point respectively in different groups. The rats were transcardially perfused with 4% paraformaldehyde on postoperative 48 h, 7 d, 15 d and 30 d respectively and the spinal cords of L4 to L6 were harvested. X-gal staining, bcl-2 in situ hybridization and immunohistochemical staining, TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) staining and AChE (acetyl cholinesterase) histochemical staining were used. We observed that the exogenous lacZ gene was expressed in the spinal cord of Ad/lacZ group, and sense bcl-2 significantly decreased the number of apoptotic motoneurons and the decreasing degree of AChE activity of the motoneurons in the spinal cord induced by sciatic nerve axotomy and accelerate AChE activity recovery. However, antisense bcl-2 increased the number of apoptotic motoneurons and the decreasing degree of AChE activity of the motoneurons in the spinal cord induced by sciatic nerve axotomy and prolonged AChE activity recovery. These results demonstrate that exogenous bcl-2 may protect motor neurons from injury induced by peripheral nerve axotomy.

Adenoviridae↗
PubMed1991

Ultrastructural changes in the nucleolus of facial motor neurons following axotomy during an early critical period in development.

In this study, the effects of axotomy on the ultrastructure of the nucleolus and associated organelles were examined in fetal, newborn, and early postnatal facial motoneurons of the hamster. Golden hamsters used for this study were the 14-day fetus, newborn (0 days; less than 6 hr) and 2, 4, 7, and 9 days postnatal ages, with 3 animals per group. For prenatal surgeries, pregnant hamsters were anesthetized and the facial nerves severed in the fetuses via electrocautery through the uterine wall and amniotic membrane. For postnatal surgeries, the animals were anesthetized and the right facial nerve exposed and severed at its exit from the stylomastoid foramen. At the appropriate postoperative times, the animals were reanesthetized and perfused-fixed. The facial nuclear groups were dissected and processed for routine electron microscopy. Microbody and coiled body frequencies were determined from the number of neurons containing these structures per number of neurons sampled per animal in each experimental or control group and subjected to statistical analysis. Nucleolar reactive changes that occurred during this developmental sequence fell into two major categories. The first category displayed by most injured cells consisted of an initial compacting of fibrillar material and reduction in vacuolar space. The second category appeared to represent a progression from this first stage of nucleolar reactivity into degenerative changes involving a striking segregation of nucleolar components into five distinct regions. The incidence of microbodies increased as a result of axotomy, whereas the presence of coiled bodies decreased at the later postoperative stages in the older animals. With increasing age and nucleolar maturation, the nucleolar reactive pattern became less pronounced and severe, and neuronal survival predominated. It appears, therefore, that the two categories of nucleolar changes following axotomy during early development correlate with changes observed in nucleoli under conditions of rRNA downregulation. It is hypothesized from these results that a key step in the ability of neurons to survive axotomy and successfully regenerate at these early developmental stages occurs at some point in ribosomal RNA transcription and/or processing. Complementary information at the molecular level concerning changes in nucleolar synthetic activity and ribosome production will be necessary to test this hypothesis.

Animals↗
PubMed1992

Changes in size and dendritic arborization patterns of adult cat spinal alpha-motoneurons following permanent axotomy.

This study was performed to analyse quantitatively the changes in dimensions and dendritic branching patterns of adult cat spinal alpha-motoneurons following permanent axotomy, i.e., in a situation in which the transected motoraxons are prevented from reinnervating their peripheral target muscle. After transection and ligation of the medial gastrocnemius nerve of adult cats, homonymous alpha-motoneurons were intracellularly labelled with horseradish peroxidase and subjected to quantitative light microscopic analyses. The cell bodies and proximal dendrites were studied at 3, 6, and 12 weeks after the axotomy. An initial increase in cell body size at 3 weeks was followed by a gradual return towards normal values. The mean diameter of the stem dendrites was decreased at all time periods studied, and the combined diameter of the stem dendrites was reduced at 12 weeks after the axotomy. Entire dendritic trees were reconstructed at 12 weeks postoperatively, and the regression equations describing the correlations between dendritic stem diameter, on one hand, and the size of the entire dendrite, on the other, were used to calculate the total dendritic length, volume, and membrane area of whole axotomized motoneurons. The dendritic branching patterns were also analysed. In comparison with normal medial gastrocnemius alpha-motoneurons, the dendritic membrane area and volume of the axotomized cells had decreased by 36% and 29%, respectively, at 12 weeks after the axotomy. This reduction in dendritic size was due to a loss of preterminal and terminal dendritic segments. Abnormal dendritic elongations were observed in 2 of 16 completely reconstructed dendrites.

Analysis of Variance↗
PubMed1995

Secretory pathways of neuropeptides in rat lumbar dorsal root ganglion neurons and effects of peripheral axotomy.

Using immunocytochemistry combined with confocal and electron microscopy, the secretory pathways related to substance P (SP), calcitonin gene-related peptide (CGRP), galanin (GAL), and neuropeptide Y (NPY) were investigated in neurons in rat lumbar (L) 4 and L5 dorsal root ganglia (DRGs) before and after peripheral axotomy. All four peptides were processed through the regulated secretory pathway in many small neurons in normal DRGs, and CGRP through this pathway also in some large neurons. In many small neurons, two neuropeptides could be sorted into the same or separate large dense-core vesicles (LDCVs). The LDCVs had a significantly larger diameter in small as compared to large DRG neurons. Fourteen days after sciatic nerve cut, the levels of SP- and CGRP-like immunoreactivities (-LIs) and the number of LDCVs containing these peptides were markedly reduced, but SP- and CGRP-LIs were still seen in the regulated pathway. GAL-LI was markedly increased in many small neurons and some large neurons and NPY-LI mainly in large neurons. Both peptides were particularly abundant in the Golgi region. In small neurons, the number of LDCVs containing GAL- or NPY-LI was increased, but did not appear to reach the numbers containing SP- or CGRP-LI in normal DRG neurons. After axotomy, CGRP-LI and GAL-LI were often in separate LDCVs. One type of NPY-positive large neurons showed budding off of LDCVs after axotomy, but also some "scattered" labeling in the cytoplasm. In the second type, NPY-LI was mainly found in multivesicular bodies. In several myelinated nerve fibers a "diffuse" distribution of NPY was seen together with some LDCVs containing NPY-LI. In contrast, in unmyelinated nerve fibers, NPY-, GAL-, SP-, and CGRP-LIs were always observed in LDCVs. Thus, both in normal and axotomized DRG neurons, peptides are processed through the regulated pathway. However, in some large neurons, NPY is, in addition, secreted through the constitutive pathway, perhaps as a consequence of limited sorting mechanisms for NPY, i.e., the plasticity of the secretory mechanisms does not match the rate of peptide synthesis after axotomy.

Animals↗
PubMed1995

Reorganization of central terminals of myelinated primary afferents in the rat dorsal horn following peripheral axotomy.

We have investigated the time course and extent to which peripheral nerve lesions cause a morphological reorganization of the central terminals of choleragenoid-horseradish peroxidase (B-HRP)-labelled primary afferent fibers in the mammalian dorsal horn. Choleragenoid-horseradish peroxidase is retrogradely transported by myelinated (A) sensory axons to laminae I, III, IV and V of the normal dorsal horn of the spinal cord, leaving lamina II unlabelled. We previously showed that peripheral axotomy results in the sprouting of numerous B-HRP-labelled large myelinated sensory axons into lamina II. We show here that this spread of B-HRP-labelled axons into lamina II is detectable at 1 week, maximal by 2 weeks and persists for over 6 months postlesion. By 9 months, however, B-HRP fibers no longer appear in lamina II. The sprouting into lamina II occurs whether regeneration is allowed (crush) or prevented (section with ligation), and does not reverse at times when peripheral fibers reinnervate the periphery. We also show that 15 times more synaptic terminals in lamina II are labelled by B-HRP 2 weeks after axotomy than in the normal. We interpret this as indicating that the sprouting fibers are making synaptic contacts with postsynaptic targets. This implies that A-fiber terminal reorganization is a prominent and long-lasting but not permanent feature of peripheral axotomy. We also provide evidence that this sprouting is the consequence of a combination of an atrophic loss of central synaptic terminals and the conditioning of the sensory neurons by peripheral axotomy. The sprouting of large sensory fibers into the spinal territory where postsynaptic targets usually receive only small afferent fiber input may bear on the intractable touch-evoked pain that can follow nerve injury.

Afferent Pathways↗
PubMed1990

Rat facial motoneurons express increased levels of calcitonin gene-related peptide mRNA in response to axotomy.

The expression and localization of the mRNA encoding the calcitonin gene-related peptide (CGRP) were analyzed in the rat facial nucleus after axotomy by Northern blot analysis and by in situ hybridization histochemistry (ISH) using a synthetic 32P-labeled oligonucleotide probe. Northern blot analysis revealed the presence of the 1.2 kb CGRP mRNA in RNA extracted from the facial nucleus. This mRNA species was strongly increased after axotomy of the facial nerve. By ISH increased levels of CGRP mRNA were observed as soon as 16 hr after axotomy compared with the unoperated nucleus. CGRP mRNA could be localized in more than 50% of the motoneurons. Three populations of motoneurons with no, moderate, or strong labeling for CGRP mRNA could be distinguished. Peak expression of CGRP mRNA during the first 48 hr was followed by a decline to moderate levels at day 4 after lesion, and to almost basal levels at days 7 and 9. These data demonstrate that axotomy of the facial nerve leads to an early and strong induction of CGRP gene expression in motoneurons of the facial nucleus.

Amino Acid Sequence↗
PubMed1992

Deprenyl reduces the death of motoneurons caused by axotomy.

Deprenyl, a monoamine oxidase B inhibitor, appears to slow the progression of neurological deficits in Parkinson's disease and cognitive decline in Alzheimer's disease. The mechanisms for the slowing of the diseases are unknown. Deprenyl can reduce the death of murine substantia nigra neurons when administered after the neurons are damaged in MPTP parkinsonism by increasing the neurons' survival after they are damaged, rather than by just protecting the neurons against damage by blocking the conversion of MPTP to its active form as was previously thought. The death of immature motoneurons after separation from their muscle targets by axotomy provides a model for assessing trophically dependent neuronal survival. To determine whether deprenyl can alter the survival of neurons other than those in the substantia nigra, we examined the survival of rat facial motoneurons after axotomy at 14 days of age. Using a combination of immunocytochemistry for choline acetyl transferase and Nissl staining, we found that deprenyl treatment (10 mg/kg every second day) increased by 2.2 times the number of motoneurons surviving 21 days after the axotomy. This finding showed that deprenyl treatment can rescue neurons other than those in the substantia nigra and can compensate in part for the loss of target-derived trophic support caused by axotomy.

Animals↗
PubMed1986

Differential time course of the response to axotomy induced by cut or crush in the leech AP cell.

The time course of the reaction to axotomy in the leech AP cell was determined by measuring the duration of the spontaneous spikes at different times after the operation. The axotomy performed by section of the segmental roots containing the AP axon induced an increase of the spike duration, which persisted over 30 days. A different time course was found when the axotomy was performed by nerve crush: the changes in duration of the spontaneous spikes, which occurred during the early 2 weeks, were significantly reduced afterwards. Dye staining of some cells axotomized by crushing revealed that the reversion of the changes, which had been set up by axotomy, was in some cases concomitant with the reconnection between proximal and distal axon stumps. The section of a single axonal branch was never sufficient to affect the membrane properties of the AP cells. It is concluded that the changes observed in axotomized AP cells are not produced by simple axonal injury and that the maintainance of normal properties in the somatic membrane requires the presence of at least part of the distal axon arborization.

Animals↗
PubMed1993

Regulation of substance P is similar to that of vasoactive intestinal peptide after axotomy or explantation of the rat superior cervical ganglion.

The regulation of the expression of substance P (SP) in the rat superior cervical ganglion was compared to that of vasoactive intestinal peptide (VIP) in vivo after axotomy and in vitro after explantation. Previous studies have demonstrated that both neuropeptides increase after explantation, depolarization, and decentralization; however, whereas VIP expression increases after postganglionic axotomy, SP expression reportedly does not. To compare the effect of axotomy on these two peptides directly, the content of both was determined in individual ganglia at various times after surgery. The level of VIP-like immunoreactivity (IR) is increased at 2 days, reaches a peak at 6 days, and then declines by 14 days to approximately half its peak value. The level of SP-IR also increases 2 days after axotomy, but returns to control values by day 6. The increase in SP-IR is accompanied by an increase in beta-preprotachykinin mRNA, suggesting that the elevation in SP content is due, at least in part, to enhanced peptide synthesis. Immunocytochemical localization of SP-IR revealed the presence of immunoreactive principal neurons in axotomized, but not in sham-operated ganglia. Similarities in the regulation of these two neuropeptides were also investigated in organ culture by examining the effects of dexamethasone and interleukin-1 beta on VIP content, since the former has been shown to prevent the increase in SP in culture, while the latter has been found to enhance this increase (Kessler, Adler, Bell, et al., 1983, Neuroscience 9:309-321; Freidin and Kessler, 1991, Proc. Natl. Acad. Sci. USA 88:3200-3203; Hart, Shadiack, and Jonakait, 1991, J. Neurosci. Res. 29:282-291). As with SP expression, dexamethasone reduces the increase in VIP expression, while interleukin-1 beta increases it. Thus, both in vivo and in vitro, similar changes in VIP and SP expression are observed following a number of experimental manipulations, suggesting that expression of the two peptides is regulated by qualitatively similar mechanisms in sympathetic neurons.

Animals↗