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PubMed1998

Block by picrotoxin of a GABAergic chloride channel expressed on crayfish muscle after axotomy.

Outside-out patches containing a gamma-aminobutyric acid (GABA)-activated chloride channel expressed after axotomy on crayfish deep extensor abdominal muscle were excised. GABA and the blocker picrotoxin (PTX) were applied to the patches using a liquid filament switch to study the effects of picrotoxin on the GABA-elicited currents. Coapplication of GABA and PTX resulted in a reduction of the current amplitude compared with that elicited by the same GABA concentration alone. This reduction of the amplitude was dependent on both the GABA and PTX concentrations. The rise time of the current decreased after coapplication of GABA and PTX. Evaluation of the single channel currents and off-currents in the presence of GABA and PTX showed a dramatic shortening of the burst duration of the channel. The open time distributions were not altered, whereas in the closed time distributions a new closed time was apparent in presence of PTX. Preincubation with PTX prior to the GABA pulse resulted in an increase of the rise time. This effect was dependent on the PTX concentration only. Possible mechanisms are discussed to explain the effects of PTX and are implemented into the existing molecular reaction scheme of the channel.

Animals↗
PubMed1998

NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy.

Although physiological and pharmacological evidence suggests the presence of multiple tetrodotoxin-resistant (TTX-R) Na channels in neurons of peripheral nervous system ganglia, only one, SNS/PN3, has been identified in these cells to date. We have identified and sequenced a novel Na channel alpha-subunit (NaN), predicted to be TTX-R and voltage-gated, that is expressed preferentially in sensory neurons within dorsal root ganglia (DRG) and trigeminal ganglia. The predicted amino acid sequence of NaN can be aligned with the predicted structure of known Na channel alpha-subunits; all relevant landmark sequences, including positively charged S4 and pore-lining SS1-SS2 segments, and the inactivation tripeptide IFM, are present at predicted positions. However, NaN exhibits only 42-53% similarity to other mammalian Na channels, including SNS/PN3, indicating that it is a novel channel, and suggesting that it may represent a third subfamily of Na channels. NaN transcript levels are reduced significantly 7 days post axotomy in DRG neurons, consistent with previous findings of a reduction in TTX-R Na currents. The preferential expression of NaN in DRG and trigeminal ganglia and the reduction of NaN mRNA levels in DRG after axonal injury suggest that NaN, together with SNS/PN3, may produce TTX-R currents in peripheral sensory neurons and may influence the generation of electrical activity in these cells.

Amino Acid Sequence↗
PubMed2001

Inhibition of axotomy-induced neuronal apoptosis by extracellular delivery of a Bcl-XL fusion protein.

Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegenerative disease, and trauma. To test a new anti-apoptosis strategy for neuroprotection, we engineered nontoxic components of anthrax toxin into a Bcl-XL delivery system. Delivery of Bcl-XL by this system prevented apoptosis of cultured rat cerebellar granule cells and macrophages, and the prevention depended on both the Bcl-XL and the anthrax toxin receptor binding/translocation moieties. Furthermore, neuronal death in vivo in a retinal ganglion cell model of axotomy-induced apoptosis was inhibited by administration of this fusion protein. Thus, Bcl-XL protein can be delivered into cells from the medium or interstitial space, offering a new way to block apoptosis upstream of many caspases and the mitochondria dysfunction phase of apoptosis.

Animals↗
PubMed1998

TrkA expression in mouse olfactory tract following axotomy of olfactory nerves.

The olfactory bulb is one of the brain regions that synthesizes the nerve growth factor (NGF). Functional roles of the bulbar NGF remain to be determined. The aim of the present study was, using an antibody specific to the high-affinity NGF receptor (trkA), to examine immunohistochemically the distribution of the NGF receptor in the mouse olfactory tract, under normal conditions and during regenerative processes. In normal mouse olfactory epithelia, trkA immunoreactive cell bodies were only seen in basal cells. Cell bodies of olfactory receptor cells did not express trkA immunoreactivity, but their neuronal processes (olfactory nerve fibres and bundles in the olfactory mucosa and the olfactory bulb) displayed trkA immunoreactivity. After axotomy of olfactory nerves, regenerating olfactory cells (basal cells and olfactory receptor cells) expressed trkA immunoreactivity in intramucosal and intrabulbar neuronal processes of olfactory receptor cells. These results suggest involvement of the bulbar NGF in the process of synaptogenesis and/or regeneration of the olfactory nervous system.

Animals↗
PubMed1997

TRH-analog, TA-0910 (3-methyl-(s)-5,6-dihydroorotyl-L-histidyl-L-prolinamide) rescues motor neurons from axotomy-induced cell death.

TA-0910 (3-methyl-(s)-5,6-dihydroorotyl-L-histidyl-L-prolinamide) is a potent and long acting TRH analog. We have studied the effect of TA-0910 on axotomy-induced neuronal death. The left sciatic nerve was transected in neonatal rats. TA-0910 or vehicle was administered on consecutive 14 days with intraperitoneal injections. After the treatment, the number of spinal motor neurons and the motor neuron diameter was assessed at the level of L4-6 segments. In comparison with vehicle, TA-0910 significantly prevented the death of motor neurons and preserved the motor neuron diameter on the lesioned side. These results suggest that TA-0910 is a survival factor for developing spinal motor neurons.

Animals↗
PubMed2004

Newly-formed axonal branches of rat sciatic neurons sprouting in the spinal cord after peripheral axotomy.

A retrograde method of nerve tracing using a recombinant adenovirus was applied to experimental regeneration of peripheral nerves to study the sprouting position of the regenerating axon. This enabled us to see the entire length of the axons on a whole-mount neural specimen. The peroneal nerve was transsected and infected with this virus, and the tibial nerve was transsected and sutured in eight Wistar rats. Four to five weeks later, labelled axons appeared in the tibial nerve, some of which could be traced from the tibial nerve to the spinal cord without making a connection with other labelled fibres. Control experiments negated the possibilities of transneuronal immigration or contamination of the virus. When the peroneal and tibial nerves were double-labelled with fluorescent tracers four weeks after their transsection, double-labelled motor neurons appeared. Based on these findings, we conclude that regenerating branches do sprout in the spinal cord after axotomy.

Adenoviridae↗
PubMed2000

Death commitment point is advanced by axotomy in sympathetic neurons.

Axotomized neurons have several characteristics that are different from intact neurons. Here we show that, unlike established cultures, the axotomized sympathetic neurons deprived of NGF become committed to die before caspase activation, since the same proportion of NGF-deprived neurons are rescued by NGF regardless of whether caspases are inhibited by the pan-caspase inhibitor Boc-Asp(O-methyl)-CH(2)F (BAF). Despite prolonged Akt and ERK signaling induced by NGF after BAF treatment has prevented death, the neurons fail to increase protein synthesis, recover ATP levels, or grow. Within 3 d, all the mitochondria disappear without apparent removal of any other organelles or loss of membrane integrity. Although NGF does rescue intact BAF-treated 6-d cultures after NGF deprivation, rescue by NGF fails when these neurons are axotomized before NGF deprivation and BAF treatment. Moreover, cytosolic cytochrome c rapidly kills axotomized neurons. We propose that axotomy induces signals that make sympathetic neurons competent to die prematurely. NGF cannot repair these NGF-deprived, BAF-treated neurons because receptor signaling (which is normal) is uncoupled from protein renewal, and the mitochondria (which are damaged) go on to be eliminated. Hence, the order of steps underlying neuronal death commitment is mutable and open to regulation.

Adenosine Triphosphate↗
PubMed1999

The novel pyrrolopyrimidine PNU-101033-E improves facial motor neuron survival following intracranial axotomy of the facial nerve in the adult rat.

Neuronal survival is important to functional restitution following axotomy. Proximal lesions of the facial nerve, due to head trauma or tumor growth, for example, may cause long-standing or even permanent facial nerve palsy. Betamethasone has been used by several neurosurgical clinics for the treatment of postoperative facial nerve palsy; however, this practice is based only on clinical experience. The aim of the present study was to explore the putative effect on facial motor neuron survival of a novel lazaroid (pyrrolopyrimidine, PNU-101033-E) and furthermore to compare the effects with those of betamethasone, following intracranial transection of the facial nerve in adult rats. Both agents are known to inhibit lipid peroxidation by free radical scavenging. The lesion model used has recently been reported to induce massive neuronal cell death with a relative survival of 26.8 +/- 11.3% 1 month after lesion. Oral administration of lazaroids or daily injections of betamethasone followed surgery for 1 month, after which quantification of motor neuronal profiles was performed in the facial nucleus. Lazaroid-treated animals showed a significantly enhanced neuronal survival (68.0 +/- 9.8%), whereas no significant difference was found in betamethasone-treated animals (33.1 +/- 11.7%). The microglial and astrocytic responses in the facial nucleus were intense on the operated sides in betamethasone-treated as well as lazaroid-treated animals, and no differences in comparison with untreated animals were found. In conclusion, we found that the novel pyrrolopyrimidine PNU-101033-E, but not betamethasone, significantly enhanced nerve cell survival. This agent may therefore serve as a useful neuroprotective agent following intracranial trauma to the facial nerve and should be further evaluated for clinical use.

Animals↗
PubMed2000

Sequence of cellular changes following localized axotomy to cortical neurons in glia-free culture.

This study utilizes an in vitro model of localized physical injury to axons to examine the specific responses of neocortical neurons to trauma in isolation from glia cell types. The neuronal response to axotomy was closely linked with nerve cell maturity. Cultures grown for 14 days in vitro showed no accumulation of either neurofilaments or, the axonal sprouting marker, GAP43, within injured axons following injury. In older cultures (21 days in vitro), however, temporally distinct axonal changes were evident following transection of axonal bundles. At 12 h postinjury, these included extensive accumulation of neurofilaments into ring-like structures within the cut stumps and an increase in punctate GAP43 labelling throughout the damaged area. At 24 h postinjury, bulb-like accumulations of neurofilaments were also present within the transected axons. Finally at 3 days postinjury, distinct GAP43 and neurofilament immunolabeled axons, and GAP43 immunopositive growth cones, emanated from the cut stump. These results indicate that injured axons of mature neurons undergo a defined series of reactive changes, ultimately culminating in a sprouting response, which occur independently of the presence or effects of glial cell populations.

Animals↗
PubMed2005

Mild axonal stretch injury in vitro induces a progressive series of neurofilament alterations ultimately leading to delayed axotomy.

We report a new model of transient axonal stretch injury involving pressurized fluid deflection of bundles of axons, resulting in a transient 1-6% increase in original axon length to investigate the slow progression of axonal alterations that are characteristic of diffuse axonal injury (DAI). We found no discernable difference in axon bundle morphology or cytoskeletal neurofilament protein arrangement between unstretched and stretched axonal bundles at 24 h post-injury. However, by 48 h post-injury, there was a stereotypical response of stretched axons involving characteristic neurofilament alterations that bear similarities to in vivo neuronal responses associated with DAI that have been reported previously. For instance, neurofilament protein immunoreactivity (SMI-312) was increased in axons contained within 51% of all injured axon bundles at 48 h compared to surrounding unstretched axon bundles, suggestive of neurofilament compaction. Furthermore, axonal bundle derangement occurred in 25% of injured axon bundles, with individual fibres segregating from each other and becoming undulating and wavy. By 72 h post-stretch, 70% of injured axon bundles underwent secondary axotomy, becoming completely severed at the site of initial stretch injury. While these results suggest a temporal series of stereotypical responses of axons to injury, we were able to distinguish very clear differences between mildly (100-103% increase in original axonal length) injured and strongly injured (106%+) axons. For instance, mildly injured axons developed increased neurofilament immunoreactivtity (SMI-312) within 48 h, and the marked development of ring-like neurofilament immunoreactive structures within axonal bundles, which were rarely axotomized. Conversely, at more severe strain levels increased neurofilament immunoreactivity was less apparent, while axons often became distorted and disorganised within axonal bundles and eventually became completely disconnected. Almost no ring-like neurofilament structures were observed in these severely injured axonal bundles. This suggests that axons do not respond in a stereotypical manner to a transient stretch insult, and indeed that variable degrees of stretch injury activate different responses within axons, with dramatically different outcomes. Hence, it is possible that the cytoskeletal characteristics that we have used in this study may be useful parameters for discriminating between mildly and severely injured axons following TBI.

Animals↗
PubMed2005

Down-regulation of apoptosis mediators by RNAi inhibits axotomy-induced retinal ganglion cell death in vivo.

Transection of the optic nerve induces an apoptotic degeneration of retinal ganglion cells (RGC) in the rat retina. The immediate early gene c-Jun, the proapoptotic Bcl-2 family member Bax and the apoptosome constituent Apaf-1 have been shown previously to play major roles in the induction or execution of the apoptosis cascade. In this study we have designed and generated short interfering RNAs (siRNAs) against c-Jun, Bax and Apaf-1, which were injected into the optic nerve stump in order to inhibit axotomy-induced apoptosis. siRNAs were first tested in vitro to ensure silencing efficiency. In vivo, a clear neuronal localization of Cy3-labelled siRNA could be visualized in retinal flat mounts. Retinas that were injected with anti-Apaf-1- and anti-c-Jun-siRNA showed significantly more surviving RGC than non-injected or anti-EGFP-injected controls (approximately 2- to 3-fold, respectively). Anti-Bax-siRNA-injected retinas showed a trend towards an increased RGC number (not significant). Regulation of target proteins in situ could be visualized by immunohistochemical stainings. We conclude that (i) c-Jun and Apaf-1 play major roles in the apoptotic cascade of RGC and may represent useful targets for antiapoptotic strategies in RGC in vivo, and (ii) injection of siRNAs into the optic nerve stump is a new method to down-regulate target genes specifically in RGC.

Animals↗
PubMed2001

Matrix metalloproteinase expression and inhibition after sciatic nerve axotomy.

Wallerian degeneration is characterized by breakdown of myelin and axons with subsequent macrophage infiltration and removal of the degenerating nerve components. Proteinases of the matrix metalloproteinase (MMP) family seem to play an important role in demyelinating processes, since some of their members have been shown to cleave myelin basic protein. In the present study we investigated the expression of MMP-2 and MMP-9 (gelatinases A and B) during myelin removal after peripheral nerve trauma. After transection of the sciatic nerve an upregulation of MMP-2 and MMP-9 with a first peak 12 h and a second peak 48 h after axotomy was observed by zymography. These peaks correlate with the breakdown of the blood-nerve barrier, the accumulation of granulocytes, and the invasion of macrophages into the damaged nerves, respectively. Furthermore, MMP-2 was found to be upregulated in the contralateral nontransected nerves. Immunocytochemistry for MMP-9 and in situ zymography identified MMP-reactive cells within the distal nerve stump. Chloracetate esterase staining was used to detect granulocytes, which accumulated at the transection site and were colocalized with the in situ zymography signal. Wallerian degeneration of the transected nerve could be delayed either by intraperitoneal injections of hydroxamate (Ro 31-9790), a nonspecific MMP inhibitor, or by local application of an MMP-9-specific antibody. Following these treatment strategies, a decreased number of invading macrophages was seen in the nerves associated with an increased amount of preserved myelin sheaths. These results suggest that the invasion of macrophages into a transected peripheral nerve is accompanied by an increased expression of MMPs, particularly MMP-9. Thus, MMPs may seem to play an important role in the breakdown of the blood-nerve barrier and subsequent cell recruitment from the systemic circulation into the damaged nerve.

Animals↗
PubMed1998

Sensory neurons regenerate more dominantly than motoneurons during the initial stage of the regenerating process after peripheral axotomy.

This study was designed to determine whether sensory neurons or motoneurons were dominant during the earlier stage of the regeneration process after peripheral axotomy. After transection of the right sciatic nerves of rats, epineurial end neurorrhaphy was performed. At 5, 7 and 14 days postoperatively, the nerves were re-transected at the positive pinch site, and their proximal stumps were exposed to the retrograde neurotracer, Fluoro-Gold (F-G). Seventy-two hours later, the lumbar spinal cords and the L4 and L5 dorsal root ganglia (DRG) were harvested and evaluated. The incidence and the intensity of F-G labelling in DRG were significantly higher than in anterior horns (AH). These results demonstrated that sensory neurons were more dominant than motoneurons in nerve regeneration.

Animals↗
PubMed1999

Changes in the action potential in sensory neurones after peripheral axotomy in vivo.

Following nerve injury, modified somatic ion channels may underlie ectopic activity in axotomized A-type neurones in dorsal root ganglia (DRGs) leading to abnormal pain signalling. Using intracellular microelectrodes both in vivo and in vitro, action potentials (APs) were recorded in rat DRG neurones classified by axonal conduction velocity. After lesions to L5 spinal or sciatic nerves, APs in both A alpha/beta and A delta cells were wider, and those in A alpha/beta neurones more frequently showed inflections during repolarization, than APs in cells in undamaged ganglia. AP amplitudes and dV/dt(max) were not significantly altered by axotomy. These results confirm previous observations in intact ganglia in vitro but differ from those reported for dissociated neurones using patch recording techniques.

Action Potentials↗
PubMed2000

Peripheral axotomy increases cholecystokinin release in the rat anterior cingulate cortex.

The anterior cingulate cortex (ACC) is a limbic region with a high density of cholecystokinin (CCK) immunoreactivity, that has been suggested to be of importance for the affective and emotional component of pain. In the present microdialysis study, performed in the awake rat, we demonstrate a bilateral 4- to 6-fold increase of the potassium-induced release of CCK-like immunoreactivity (CCK-LI) in the ACC 2-3 weeks after a unilateral transection of the sciatic nerve (axotomy), an animal model of phantom limb or deafferentiation pain. Considering the implication of CCK in pain modulation and anxiety, we suggest that an altered activity of CCK containing neurons in the ACC may be of importance for the affective component of certain pain conditions.

Animals↗
PubMed2004

Semaphorin and neuropilin expression in motoneurons after intraspinal motoneuron axotomy.

We have examined mRNA and protein distribution for the axon guidance molecules semaphorin3A, 3F, 4F and semaphorin receptors neuropilin-1 and 2, 1-21 days after intramedullary axotomy of rat lumbar spinal cord motoneurons. We show that semaphorin3A mRNA and protein are up-regulated in the scar and in motoneurons from 3 days and upto 3 weeks after injury. Neuropilin-1 mRNA showed no changed expression in axotomized motoneurons. Semaphorin3F mRNA expression was found in ventral roots after ventral funiculus lesion (VFL) and neuropilin-2 mRNA was found in affected motoneurons from 1 day after injury throughout the examined period. Semaphorin4F mRNA was first found in motoneurons 3 weeks after lesion. These results suggest semaphorin/neuropilin involvement in the injury response of intramedullary axotomized motoneurons.

Animals↗
PubMed2007

The Rho-associated kinase inhibitor fasudil hydrochloride enhances neural regeneration after axotomy in the peripheral nervous system.

BACKGROUND: The Rho family of small GTPases is responsible for various processes involving actin cytoskeleton in eukaryotic cells, including neurite outgrowth. Several substances found at the peripheral nerve injury site were shown to activate one member of this family, Rho. The activation of Rho leads to neurite outgrowth inhibition and the development of posttraumatic neuropathic pain. The authors used the clinically tested Rho-associated kinase inhibitor fasudil hydrochloride to enhance the functional recovery of the peripheral nerve in the rat. METHODS: In the peroneal nerve interpositional graft model, the authors administered fasudil (experimental groups) or saline (control groups) (1) intraperitoneally and (2) directly into the graft by microinjection (n = 6 animals per experimental condition). Neural recovery was assessed during postoperative follow-up lasting 80 days by peroneal functional index, electrophysiologic, and histomorphometric analyses. RESULTS: The peroneal functional index returned to values not significantly different from preoperative values on days 55 (fasudil injected into the graft) and 60 (fasudil injected intraperitoneally) in the experimental groups. In the control groups, this took 70 (saline injected intraperitoneally) and 75 days (saline injected into the graft). These results are supported by electrophysiologic and histomorphologic assessments. CONCLUSIONS: The authors determined that fasudil hydrochloride was capable of accelerating the functional regeneration after peripheral nerve axotomy, which is consistent with the results of reports about Rho cascade disruption in the central nervous system. Because fasudil hydrochloride is a clinically tested drug, it could be used to enhance neural regeneration in human patients as well.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Impairment of axotomy-induced pituitary adenylyl cyclase-activating peptide gene expression in T helper 2 lymphocyte-deficient mice.

CD4+ (T helper) lymphocytes appear to play important roles in neuron survival and regeneration after injury, although their functions in regulating gene expression in injured neurons are unknown. Mice with targeted mutations in the STAT4 and STAT6 genes are deficient in T helper (Th)1 and Th2 responses, respectively, and have been used to determine the relative importance of T helper subsets in a variety of inflammatory processes. As pituitary adenylyl cyclase-activating peptide mRNA is normally strongly induced in facial motor neurons after axotomy, we examined this induction in Th1 and Th2 lymphocyte-deficient and control Balb/C wild-type mice. As previously reported, pituitary adenylyl cyclase-activating peptide gene expression was strongly induced in ipsilateral but not contralateral motor neurons in the facial motor nucleus of wild-type mice. The mean number of hybridizing motor neurons in STAT4-deficient mice did not differ from that in wild-type mice, whereas the number in STAT6 mice was reduced by more than 50%. The results indicate that STAT6 plays a key role in the upregulation of pituitary adenylyl cyclase-activating peptide gene expression in facial motor neurons after injury, possibly through its role in regulating T helper cell differentiation to the type 2 phenotype.

Animals↗