Biomedical subjects

H Aldskogius

Publications and source records attributed to H Aldskogius.

At least 37 records · Page 2Linked to original sources

PubMed1997

Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR.

The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.

Animals↗

PubMed1997

Comprehensive immunofluorescence and lectin binding analysis of intervibrissal fur innervation in the mystacial pad of the rat.

The innervation of the intervibrissal fur in the mystacial pad of the rat and mouse was examined by immunofluorescence with a wide variety of antibodies for neuronal related structural proteins, enzymes, and peptides as well as for lectin binding histofluorescence with Griffonia simplicifolia (GSA). Anti-protein gene product 9.5 (PGP) immunofluorescence labeled all sets of axons and endings. The innervation in the upper dermis and epidermis was distributed through a four tiered dermal plexus. From deep to superficial, the second tier was the source of all apparent myelinated mechanoreceptors, the third tier of nearly all the peptidergic and GSA binding innervation, and the fourth tier of nonpeptidergic GSA negative innervation (peptide-/GSA-). Three types of mechanoreceptors-Merkel, transverse lanceolate, and longitudinal lanceolate endings-innervated guard hair follicles. All had similar labeling characteristics for 160 kDa and 200 kDa neurofilament subunits, peripherin, carbonic anhydrase, synaptophysin, and S100. Palisades of longitudinal lanceolate endings were part of piloneural complexes along circumferentially oriented sets of transverse lanceolate endings, peptidergic free nerve endings (FNEs), and peptide-/GSA- FNEs. The longitudinal lanceolate endings were the only mechanoreceptors in the mystacial pad that had detectable calcitonin gene-related peptide. The epidermis contained four types of unmyelinated endings: simple free nerve endings (FNEs), penicillate endings, cluster endings and bush endings. Only the simple FNEs were clearly peptidergic. Virtually all others were peptide-/ GSA-. Each bush ending was actually an intermingled cluster of endings formed by several unmyelinated axons and occasionally an Adelta axon. In contrast to the other unmyelinated innervation to the epidermis, bush endings labeled with an antibody against the Schwann cell protein S100. The necks and mouths of follicles, as well as superficial vasculature, were innervated by a mixture of unmyelinated peptidergic and/or GSA labeled sensory and sympathetic axons. Small presumptive sweat glands were innervated by three sets of peptidergic axons of which one was immunoreactive for somatostatin. Potential functions of the various sets of innervation are discussed.

Animals↗

PubMed1997

Comprehensive immunofluorescence and lectin binding analysis of vibrissal follicle sinus complex innervation in the mystacial pad of the rat.

The innervation of the vibrissal follicle sinus complexes (FSCs) in the mystacial pad of the rat was examined by lectin binding histofluorescence with the B subunit of Griffonia simplicifolia (GSA) and by immunofluorescence with a wide variety of antibodies for neuronal related structural proteins, enzymes, and peptides. Only anti-protein gene product 9.5 labeled all sets of innervation. Several types of mechanoreceptors were distributed to specific different targets by medium to large caliber myelinated axons. All were positive for 200 kDa neurofilament subunit, peripherin, and carbonic anhydrase. Their endings expressed synaptophysin. Labeling for the 160 kDa neurofilament subunit, calbindin, and parvalbumin varied. Anti-Schwann cell protein S100 was completely co-extensive with the axons, terminal arbors, and endings of the mechanoreceptor afferents including Merkel innervation. At least 15 different sets of unmyelinated innervation were evident based upon distribution and labeling characteristics. They consisted of four basic types: 1) peptidergic; 2) GSA binding; 3) peptidergic and GSA binding; and 4) nonpeptidergic and GSA negative (peptide-/GSA-). Previous studies had not revealed that several major sets of unmyelinated innervation were peptide-/GSA-. The unmyelinated innervation had detectable peripherin but not 160 kDa or 200 kDa neurofilament subunits. GSA-positive axons uniquely lacked anti-S100 immunoreactivity. The dense circumferentially oriented unmyelinated innervation of the inner conical body contained major sets of peptide-/GSA- and GSA innervation as well as a smaller peptidergic GSA component. A small contingent of sympathetic and possibly parasympathetic innervation was affiliated with microvasculature in the FSCs. This study confirms and refutes some previous hypotheses about biochemical and morphological relationships between peripheral innervation and sensory ganglion cells.

Animals↗

PubMed1997

Pattern of synaptophysin immunoreactivity in the efferent nerve terminals of the guinea pig cochlea.

The goal of the present study was to analyze the distribution of efferent 8th nerve synaptic endings in a surface preparation of the guinea pig cochlea using synaptophysin antibodies. Employing light and confocal microscopy synaptophysin immunoreactivity was found exclusively at the base of the outer hair cells (OHCs) and the inner hair cells (IHCs) axosomatic efferent synapses. Qualitative and quantitative differences were found between the OHCs and the IHCs immunoreactivity. Efferent nerve endings innervating IHCs were comparatively smaller, more numerous and densely packed. Efferent terminals demonstrated a longitudinal gradient for the IHCs and a longitudinal and radial gradient for the OHCs. Quantitative analysis of synaptophysin immunofluorescence demonstrated a higher percentage of efferent terminals innervating the IHCs and the OHCs in the mid and basal segments of the cochlea than in the apical regions. In addition, a radial gradient from the 1st to 3rd row of OHCs was evident. The results from the present study show that the analysis of synaptophysin immunoreactivity on cochlear surface preparations allows the efferent innervation to be determined throughout the entire cochlea. This technique allows for a rapid assessment of the normal cochlea as well as after cochlear insult.

Animals↗

PubMed1997

Glial cell reactions in the spinal cord after sensory nerve stimulation are associated with axonal injury.

Astroglial and microglial reactions in the dorsal and ventral horns of the adult rat spinal cord were studied after graded electrical stimulation of the rat sciatic nerve and after topical application of mustard oil to the hindlimb foot. Antibodies to glial fibrillary acidic protein and complement receptor 3 (OX-42) were used as markers for astroglia and microglia, respectively. The results showed that electrical nerve stimulation resulted in increased immunoreactivity for GFAP and OX-42 in the spinal cord dorsal and ventral horns only after the use of stimulation strengths which were associated with nerve fiber degeneration in the stimulated nerve. Application of mustard oil to the foot caused no changes in GFAP or OX-42 immunoreactivity. These findings indicate that peripheral nerve stimulation in itself is insufficient to induce astroglial and microglial responses in the spinal cord. The signal(s) mediating these responses, regularly seen after nerve injury, are therefore most probably not related to the afferent barrage of action potentials evoked by the injury.

Animals↗

PubMed1997

A quantitative analysis of the glial cell reaction in primary sensory termination areas following sciatic nerve injury and treatment with nerve growth factor in the adult rat.

The time course of the astroglial cell reaction in the nucleus gracilis and the spinal cord dorsal horn was examined following sciatic nerve transection in the adult rat with qualitative and quantitative analysis of glial fibrillary acidic protein immunoreactivity and in situ hybridization for its mRNA. In addition, the potential effect of exogenous nerve growth factor (NGF) was examined on the astroglial and microglial cells in the spinal cord dorsal horn at certain time points following sciatic nerve transection. An increase in glial fibrillary acidic protein immunoreactivity as well as mRNA labelling was observed from 1 day after lesioning, with a peak at about 1 week and 2 days after lesioning, respectively, followed by a decline. However, NGF application during 1, 2 and 4 weeks following nerve transection did not result in any significantly reduced astroglial or microglial activity. Our results show that the astroglial cell response in the nucleus gracilis and the spinal cord dorsal horn is rapid in comparison with previously described central degenerative changes following peripheral nerve lesions (transganglionic degeneration), that the astroglial cell reaction develops concomitantly with the microglial cell reaction previously described and that the "signal" from the axotomized neurons which induces these reactions can not be prevented by exogenous NGF applied to the peripheral nerve.

Animals↗

PubMed1997

Effects of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 on the laminar distribution of transganglionically fransported choleragenoid in the spinal cord dorsal horn following transection of the sciatic nerve in the adult rat.

Spinal cord projections from transected sciatic nerves treated with different neurotrophins were investigated in the adult rat following injections of choleragenoid into the proximal stump of the injured nerve. Transganglionically transported choleragenoid labelled primary afferent fibres in all spinal cord dorsal horn laminae except the outer part of lamina II (II(o)), which is almost devoid of labelling. Transection of the sciatic nerve, however, resulted in intense transganglionic choleragenoid labelling in lamina II(o) and in lamina I. In this study, the sciatic nerve was transected bilaterally and 4erve growth factor (6 or 24 microg), brain-derived neurotrophic factor (20 microg), neurotrophin-3 (27 microg) or cytochrome C (8 microg; control substance) was applied unilaterally during postoperative survival times of eight, 16 and 32 days. The animals received bilateral injections of choleragenoid into the injured nerve two days before they were killed. The effect of the axotomy and neurotrophin treatment was evaluated by analysing the extent of choleragenoid and substance P immunoreactivity in the somatotopically appropriate spinal cord dorsal horn regions. At eight days' postoperative survival, laminae I and II(o) on the transected, non-treated side showed much more intense choleragenoid-like immunoreactivity compared to the contralateral transected, nerve growth factor-treated (6 and 24 microg) side. A similar situation was also found in cases treated with the higher dose (24 microg) at 16 days but to a lesser degree when the lower (6 microg) dose was used. After 32 days' survival, there was no detectable side difference in the choleragenoid labelling pattern. At 16 days' survival, the mean area of choleragenoid-positive ganglion cell body profiles in the L5 dorsal root ganglion of the transected, non-treated side was significantly smaller than the mean area of the transected, nerve growth factor-treated (24 microg) neurons. An axotomy-induced depletion of substance P-like immunoreactivity was seen from eight days' survival and onwards, whereas on the nerve growth factor-treated side a clearcut substance P depletion was not observed until 32 days. Brain-derived neurotrophic factor, neurotrophin-3 and cytochrome C had no detectable effects on the distribution of choleragenoid labelling or substance P-like immunoreactivity in the dorsal horn following sciatic nerve transection. In conclusion, peripheral nerve injury-induced expansion of primary afferent choleragenoid labelling in the spinal cord dorsal horn is counteracted by treating the axotomized nerve with nerve growth factor.

Animals↗

PubMed1997

Central inhibitory dysfunctions: mechanisms and clinical implications.

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

Animals↗

PubMed1997

Human dorsal root ganglion neurons from embryonic donors extend axons into the host rat spinal cord along laminin-rich peripheral surroundings of the dorsal root transitional zone.

Following dorsal root crush, the lesioned axons regenerate in the peripheral compartment of the dorsal root, but stop at the boundary between the peripheral and the central nervous system, the dorsal root transitional zone. We have previously shown that fibres from human fetal dorsal root ganglia grafted to adult rat hosts are able to grow into the spinal cord, but were not able to specify the route taken by the ingrowing fibres. In this study we have challenged the dorsal root transitional zone astrocyte boundary with human dorsal root ganglion transplants from 5-8-week-old embryos. By tracing immunolabelled human fibres in serial sections, we found that fibres consistently grow around the dorsal root transitional zone astrocytes in laminin-rich peripheral surroundings, and extend into the host rat spinal cord along blood vessels, either into deep or superficial laminae of the dorsal horn, or into the dorsal funiculus. Human fibres that did not have access to blood vessels grew on the spinal cord surface. These findings indicate, that in spite of a substantial growth capacity by axons from human embryonic dorsal root ganglion cells as well as their tolerance to non-permissive factors in the mature mammalian CNS, these axons are still sensitive to the repellent effects of astrocytes of the mature dorsal root transitional zone. Furthermore, this axonal ingrowth is consistently associated with laminin-expressing structures until the axons reach the host spinal cord.

Animals↗

PubMed1996

Growth-associated protein (GAP-43) in terminal Schwann cells of rat Pacinian corpuscles.

Growth-associated protein (GAP-43) immunoreactivity was examined in Pacinian corpuscles of intact neonatal and adult rats as well as after denervation and reinnervation in adult rats. All immature Pacinian corpuscles were GAP-43 immunoreactive (GAP-43+) in their inner cores while only 46 +/- 5.6% of the mature corpuscles exhibited GAP-43+ inner cores. The frequency of GAP-43+ inner cores increased to 90 +/- 7.2% after their permanent denervation. The expression of GAP-43 in the inner cores was reduced by contact with regrowing axons, but 38 +/- 5.3% of Pacinian corpuscles retained GAP-43+ in their inner cores following reinnervation. These results indicate that GAP-43 regulation is not confined only to axons but also involves some extra-axonal cues, and support a role for this protein in the process formation by terminal Schwann cells.

Aging↗

PubMed1996

Degeneration and regeneration of cutaneous sensory nerve formations.

Auxiliary structures of the cutaneous sensory nerve formations (SNF) are dependent on sensory innervation during their critical period of development. Denervation of mature cutaneous corpuscles results in survival of the terminal Schwann cells and the capsular structures which are probably responsible for successful reinnervation of the cutaneous SNF. In addition, the basal lamina tubes of Schwann cells are connected with the terminal Schwann cells and play an important role in the guidance of regrowing axons to their original targets. Long-lasting denervation causes atrophic changes of the terminal Schwann cells and alterations of their molecular equipment. These atrophic changes in the terminal Schwann cells may be responsible for erroneous reinnervation of cutaneous SNF. A population of the cutaneous Merkel cells surviving denervation may also serve as targets for regrowing sensory axons. The basal laminae of terminal Schwann cells are produced under control of the sensory terminals during maturation of cutaneous SNF. In adult animals, the basal laminae are capable of stimulating differentiation of migrated Schwann cells to the terminal Schwann cells without the presence of the sensory terminals. Nonspecific cholinesterase (nChE) is secreted by the terminal Schwann cells and is attached to their extracellular matrix. The synthesis of these molecules in adult animals is not influenced by the sensory terminals. However, the presence of nChE molecules is associated with living terminal Schwann cells. Fetal orthotopically grafted dorsal root ganglion (DRG) neurons have the ability to reinnervate cutaneous SNF of adult hosts. When cutaneous areas are denervated, axons from adjacent sensory nerves may extend collateral branches into this area. The capacity for such extension is dependent on: (1) type of sensory nerve ending, C and A delta fibers having significantly greater capacity than sensory axons of larger caliber; (2) age of the animal, immature animals generally showing a greater capacity for collateral sprouting; (3) the state of the adjacent axons, those already in a growth mode being more capable than "resting" ones; and (4) the regional and mechanical conditions at the site of denervation, hindpaw skin being much less extensively reinnervated by collateral fibers than that of the trunk.

Animals↗

PubMed1996

Short- and long-term transganglionic changes in the central terminations of transected vibrissal afferents in the rat.

Previous light and electron microscopic studies in rat and cat have shown that transection of peripheral sensory nerve branches leads to alterations in the central branches of primary sensory neurons, so-called transganglionic changes. In this study the changes in choleragenoid (B)-horseradish peroxidase B-HRP-labeled primary sensory terminals and axons in the trigeminal nuclear complex 3-90 days following transection of vibrissae nerves in the rat have been studied. Since regeneration of the transected vibrissa nerve was not prevented, these experiments allowed the examination of degenerative changes in the earlier stage after nerve injury as well as those present during nerve regeneration and target reinnervation. Two different experimental approaches were used, depending on the postlesion survival time. For short-term experiments the deep vibrissa nerve was injected with a solution of B-HRP. Forty-eight hours later the nerve was transected at its entry in the follicle, and after survival times ranging from 3 to 15 days sections from the subnucleus caudalis and spinal trigeminal nucleus, were prepared for electron microscopic examination. For long-term experiments involving a 16- to 90-day posttransection survival time, the deep vibrissa nerve was cut first. Then B-HRP was injected into the reinnervated follicle 2 days before killing the rats. Atypical HRP-labeled terminals were seen from 4 to 90 days survival time. The changes observed included atypical swollen vesicles or lack of vesicles in parts of the terminals apposed to the synaptic cleft. Other terminals displayed dense clusters of vesicles, flocculent cytoplasm, and/or neurofilamentous hyperplasia. No evidence of complete disintegration or phagocytosis by glial cells was observed. From 4 to 12 days survival time the changes were most commonly seen in the larger terminals, from 19-90 days in smaller terminals. From 10 days survival time and onward, changes in axons were observed. The most commonly seen alterations were axons with expanded myelin sheaths. Normal-labeled terminals were seen at all survival times examined. Compared with earlier studies of transganglionic changes in the vibrissa system occurring after infraorbital nerve or vibrissa row nerve injury, the changes seen in this study are less pronounced. These observations indicate (1) that the initial changes in the central processes of peripherally injured vibrissae nerves are less extensive than those occurring after infraorbital nerve transection, possibly because of the distally located lesion, and (2) that transganglionic changes occur also after the injured nerve has regenerated.

Afferent Pathways↗

PubMed1995

Peripherally grafted human foetal dorsal root ganglion cells extend axons into the spinal cord of adult host rats by circumventing dorsal root entry zone astrocytes.

Human foetal dorsal root ganglia were grafted in place of native lumbar dorsal root ganglia in adult rat hosts. Between 4 weeks and 4 months later, the dorsal root entry zone (DREZ) in the grafted roots showed extensive peripheral outgrowth of astrocytic processes, in contrast to the normal 'smooth' interface between the peripheral and central nervous system compartments of the DREZ. Fibres originating from the grafted neurones and approaching the DREZ changed their direction of growth and entered the spinal cord through the pia by following blood vessels, grew into the grey matter and ramified there. These findings suggest that the DREZ astrocytes in vivo are non-permissive not only to mature peripheral regenerating axons, but also to growing axons from immature neurones.

Animals↗

PubMed1995

The expression of different cytochemical markers in normal and axotomised dorsal root ganglion cells projecting to the nucleus gracilis in the adult rat.

Rat lumbar dorsal root ganglion neurones projecting to the nucleus gracilis in the brainstem were retrogradely labelled with Fluoro-Gold and analysed immunocytochemically for their expression of substance P-, calcitonin gene-related peptide-, galanin-, galanin message-associated peptide-, neuropeptide Y-, nitric oxide synthase- and carbonic anhydrase-like immunoreactivity as well as affinity to Griffonia (bandeiraea) simplicifolia lectin I--isolectin B4, RT97 and to choleragenoid. The analysis was made both in uninjured rats and in rats which had been subjected to unilateral sciatic nerve transection and partial resection 3 weeks earlier. The data showed that 6% of the L4 and L5 lumbar dorsal root ganglion cells that projected to the nucleus gracilis showed substance P-like immunoreactivity. Following nerve injury, none of the nucleus gracilis-projecting dorsal root ganglion cells showed substance P-like immunoreactivity. Nineteen per cent of the investigated cell population showed calcitonin gene-related peptide-like immunoreactivity in uninjured rats, but no nucleus gracilis-projecting calcitonin gene-related peptide-positive cells were found after nerve injury. Galanin- and galanin message-associated peptide-like immunoreactivity were found in 2% and 3%, respectively, of the Fluoro-Gold-labelled cell population normally and in 22% and 14%, respectively, after injury. No neuropeptide Y-positive cells were found in the Fluoro-Gold-labelled cell population normally, but after nerve injury, 96% of this population became neuropeptide Y-positive. Nitric oxide synthase-like immunoreactivity was found in 2% of the Fluoro-Gold-labelled cells normally and in 10% after injury. Two per cent of the Fluoro-Gold-labelled cells in the normal cases were stained by Griffonia (bandeiraea) simplicifolia lectin I--isolectin B4. After injury, however, no such double labelling was found. Thirty-four per cent of the Fluoro-Gold-labelled cell population was carbonic anhydrase positive normally, and 42% after injury. Seventy-five per cent of the Fluoro-Gold-labelled cells showed RT97 immunoreactivity normally and 12% after injury. Choleragenoid-like immunoreactivity was found in 99% of the Fluoro-Gold-labelled dorsal root ganglion cells normally and 81% after injury. Immunohistochemical visualisation of choleragenoid transganglionically transported from the injured sciatic nerve combined with neuropeptide Y immunocytochemistry showed that primary afferent fibres and terminals in the nucleus gracilis contain neuropeptide Y following peripheral nerve transection. Taken together, the results indicate that peripherally axotomised nucleus gracilis-projecting neurones undergo marked alterations in their cytochemical characteristics, which may be significant for the structural and functional plasticity of this system after injury.

Afferent Pathways↗

PubMed1995

Evidence for activation of the terminal pathway of complement and upregulation of sulfated glycoprotein (SGP)-2 in the hypoglossal nucleus following peripheral nerve injury.

In a previous study, we found immunoreactivity for complement factors C3, C3d, and C4d, as well as endogenous IgG in the hypoglossal nucleus following hypoglossal nerve transection, suggesting that activation of the complement cascade had taken place in the vicinity of the axotomized motorneurons. In the present study, we found increased immunoreactivity for complement factor C1 and C1q in reactive microglia, indicating an increased potential for initiation of the classical pathway by binding of IgG to C1q. Furthermore, we found immunoreactivity for C9, which contributes to the formation of C5b-9, the final lytic product of the complement cascade close to the axotomized neurons and perineuronal glia. In addition, immunoreactivity and mRNA labeling of sulfated glycoprotein (SGP-2), a putative complement inhibitor, was increased in a subpopulation of the axotomized motorneurons. SGP-2 immunoreactivity was also increased in astroglial cells ipsilateral to the nerve injury. The results lend further support to the hypothesis that the complement cascade is activated in the vicinity of axotomized neurons, which in turn may be protected by complement inhibitors. The balance between activation of complement and complement inhibitors might have an impact on the degenerative components of the axon reaction and, in particular, the events leading to nerve cell death.

Animals↗

PubMed1995

Peripheral target reinnervation following orthotopic grafting of fetal allogeneic and xenogeneic dorsal root ganglia.

The sensory reinnervation of dermal papillae and epidermis of glabrous skin, interosseal Pacinian corpuscles, and muscle spindles of the soleus and extensor digitorum longus muscles has been examined 1, 3, and 8 months (allografts) or 3 and 5 weeks (xenografts) following orthotopic grafting of fetal allogeneic or xenogeneic (mouse) dorsal root ganglia (DRG) into ganglionectomized adult rats. Sensory axons in target tissues were identified immunohistochemically by monoclonal antibodies against growth-associated peptide (GAP-43), heavy neurofilament protein (RT-97), anti-mouse-specific membrane glycoprotein Thy-1.2, and polyclonal antibody to calcitonin gene-related peptide (CGRP). Absence of axonal marker staining in target structures of control animals 10 days or 3 months following ipsilateral enucleation of the L3-L6 DRG without grafting indicated an elimination of host normal (intact), regenerating, or collaterally sprouting nerve fibers. The consistent finding of immunolabeled axons ending free and in encapsulated structures in the target tissues of both allo- and xenografted rats indicates that grafted primary sensory neurons can survive and send axonal processes down the full length of the hind limb, to terminate in host target tissues. Axons of xenografted fetal mouse sensory neurons grow in adult rat hosts for distances of 4 cm or more, attaining lengths far greater than called for by their normal developmental programs.

Animals↗

PubMed1995

Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat.

We provide evidence for activation of the complement cascade in the dorsal horn of the spinal cord and in the gracile nucleus in the brainstem following sciatic nerve transection in the adult rat. Immunocytochemical analyses showed immunoreactivity for endogenous immunoglobulin G as shown by immunostaining with F(ab')2 antibodies, as well as complement factors C1, C1q, C3, C3d and C9 in the appropriate central termination areas of the injured sciatic nerve. Results from double labelling immunocytochemistry showed a strong association between immunoglobulin and complement factors on the one hand and reactive microglia on the other. However, some complement immunoreactivity was also found in the neuropil, possibly representing secreted complement. In situ hybridization with an oligonucleotide probe showed a marked increase in C3 messenger RNA, indicating local synthesis of C3 protein. In parallel with activation of complement, there was an increased immunoreactivity for the putative complement inhibitor clusterin, which co-localized with glial fibrillary acidic protein-positive astrocytes. In situ hybridization showed an increased labelling of clusterin messenger RNA. These findings indicate that complement activation and up-regulation of complement inhibitors are prominent central responses to peripheral sensory nerve injury. These responses may therefore be important elements underlying so-called transganglionic degenerative changes in primary sensory axons and terminals.

Animals↗

PubMed1994

Peripherally grafted human foetal dorsal root ganglion cells extend axons into the spinal cord of adult host rats by circumventing dorsal root entry zone astrocytes.

Animals↗