Spinal cord TRH deficiency is associated with incomplete recovery of denervated muscle in the rat

Bergh, Peter Van den; Kelly, John J.; Soule, N.; Munsat, Theodore L.; Jackson, Ivor M. D.; Lechan, Ronald M.

doi:10.1212/wnl.38.3.452

Cited by 22 publications

(5 citation statements)

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“…There is also evidence for atrophic effect of TRH on motoneurons, e.g. neuronal loss following axotomy has been reported to be reduced if TRH is administered (Banda et al, 1987;Askanas et al, 1989) and ablation of the TRH bulbospinal system is associated with deficient recovery of denervated muscle (Van den Bergh et al, 1988). Furthermore, inoculation of botulinum toxin A into skeletal muscle appears to induce an increased expression of mRNA encoding TRH in medullary raphe neurons (Van den Bergh et al, 1990).…”

Section: Bulbospinal5-ht Neuronsmentioning

confidence: 99%

Calcitonin Gene‐related Peptide (CGRP)‐like Immunoreactivity and CGRP mRNA in Rat Spinal Cord Motoneurons after Different Types of Lesions

Piehl

Arvidsson

Johnson

et al. 1991

Eur J of Neuroscience

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By use of the indirect immunofluorescence (IF) technique, radioimmunoassay (RIA) and in situ hybridization (ISH) histochemistry, the staining pattern, content and expression of calcitonin gene-related peptide (CGRP) in lumbar motoneurons of normal rats and rats subjected to sciatic nerve transection (SNT), ventral root transection (VRT), low thoracic spinal cord transection (SCT) alone or in combination with a subsequent SNT, as well as rats subjected to chemical lesioning of 5-hydroxytryptamine (5-HT) neurons by 5,7-dihydroxytryptamine (5,7-DHT), were studied. We here confirm that a large number of the lumbar motoneurons normally contain CGRP-like immunoreactivity (LI) and CGRP mRNA. SNT induced a transient increase in CGRP-LI, with a peak at days 2 - 5 after lesion, and normalized levels again after approximately 2 - 3 weeks. Comparable results were obtained with IF and RIA. This increase is probably a consequence of increased CGRP synthesis, since a parallel up-regulation of CGRP mRNA levels was seen. A normalization of CGRP mRNA did not occur during the period studied, despite an apparent normalization of peptide levels after 2 weeks, and this may in turn be due to an increased turnover and/or release of CGRP. The up-regulation of CGRP is probably caused by the axon injury itself, since a similar cellular reaction with respect to CGRP was observed in motoneurons subjected to VRT. However, SNT, which also lesions dorsal root afferents and causes a decline in CGRP-LI in the dorsal horn, induced an increase in CGRP-LI in motoneurons on the contralateral side also. Thus, it may be that severance of dorsal root afferents and/or changes in reflex activity may also influence the production of CGRP in motoneurons. SCT, which severs all descending synaptic input to the motor nucleus and causes a paralysis of muscles innervated by motoneurons below the lesion, resulted in a marked decline in both content of CGRP-LI (IF and RIA) and expression of CGRP mRNA. However, treatment with 5,7-DHT, which lesions 5-HT neurons, including those giving rise to the bulbospinal serotoninergic pathway, did not cause any dramatic changes in motor behaviour but induced an increase in both motoneuron content of CGRP-LI and expression of CGRP mRNA. In rats first subjected to SCT, which depresses CGRP, followed 2 weeks later by SNT, we found a marked increase in both content of CGRP-LI (IF and RIA) and expression of mRNA coding for CGRP. In summary our results show that the cellular production of the CGRP peptide, normally expressed in motoneurons, is influenced in a complex way by motoneuron injury as well as changes in the afferent input. There also appear to be important differences in the expression of CGRP in small (gamma) and large (alpha) motoneurons as well as between motoneurons of different nuclei, in normal as well as axotomized rats.

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Section: Bulbospinal5-ht Neuronsmentioning

confidence: 99%

Calcitonin Gene‐related Peptide (CGRP)‐like Immunoreactivity and CGRP mRNA in Rat Spinal Cord Motoneurons after Different Types of Lesions

Piehl

Arvidsson

Johnson

et al. 1991

Eur J of Neuroscience

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“…Furthermore, TRH may be important for motoneuron survival and regeneration following axotomy. Thus destruction of the TRH containing bulbospinal pathway is associated with a deficient recovery of dennervated muscle (Van den Bergh et al, 1988), while inoculation of botulinum toxin A into skeletal muscles upregulates TRH mRNA expression in these raphe neurons (Van den Bergh et al, 1991). TRH may counteract the damage to motoneurons seen after intrathecal administration of the substance P antagonist Spantide (Freedman et al, 1986(Freedman et al, ,1989.…”

Section: Introductionmentioning

confidence: 99%

The serotoninergic bulbospinal system and brainstern‐spinal cord content of serotonin‐, TRH‐, and substance P‐like immunoreactivity in the aged rat with special reference to the spinal cord motor nucleus

Johnson

Ulfhake

Dagerlind

et al. 1993

Synapse

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The 5-hydroxytryptamine (5HT) containing bulbospinal pathway was studied with immunohistochemical (IF) and chemical techniques in 2-3 and 30 months old male Sprague-Dawley rats. The coexisting neuropeptides substance P (SP), thyrotropin-releasing hormone (TRH) and galanin were also analysed. Furthermore, the expression of mRNA encoding aromatic L-amino acid decarboxylase (AADC), prepro-TRH, and preprotachykinin (prepro-SP) was analysed with in situ hybridization (ISH) in the midline raphé nuclei inthe lower brainstem. The results showed a decreased number of axonal 5HT fibers with a normal morphology in the ventral horn of the aged rat lumbosacral spinal cord, and several 5HT immunoreactive (IR) fibers with an aberrant morphology, suggestive of axonal degeneration, were intermingled. This was evident in both the dorsal and ventral horn of the spinal cord. The 5HT-IR fibers with an aberrant morphology usually also contained TRH-and/or SP- and/or galanin-like immunoreactivity (LI) in the ventral horn. These signs of degeneration were clearly less evident in the thoracic and cervical spinal cord segments. Moreover, these changes varied between aged litter-mates. This was in agreement with behavioural signs of motor disturbances, present in about 40% of the aged rats and which in all cases were confined to the hindlimbs. Chemical analyses disclosed significantly lower levels of TRH-LI and, in particular, SP-LI in both the ventral and dorsal quandrants of the spinal cord in the aged rat compared to young adults. The differences were largest in the lumbar regions of the spinal cord. Corresponding analysis of 5HT and 5-hydroxyindoleacetic acid (5HIAA) in the same tissue specimens revealed largely unaltered levels of 5HT and a slight increase in 5HIAA, indicating the possibility of an increased 5HT turnover in the aged rat spinal cord. Neurons in nucleus raphé obscurus and nucleus raphé pallidus were immunoreactive to 5HT, and after pretreatment with colchicine to TRH-, SP-, and galanin-LI as well. There was no obvious difference in number of labeled cells, or labeling intensity, between colchicine-treated young adult and aged rats, although, in the corresponding region of medulla oblongata, chemical analysis disclosed significantly lower levels of 5HT, TRH, and, in particular, SP in untreated aged rats. In contrast, in situ hybridization analysis revealed increased mRNA levels encoding prepro-TRH and prepro-SP in old rats, while mRNA content encoding AADC mRNA was similar in young adult and aged rats.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Van der Berg et al (22) have shown that ablation of spinally projecting serotonergic pathways by intracisternal injection of 5,7 dihydroxytryptamine (5,7-DHT), a selective neurotoxin for serotonin neurons (23), in neonatal rats results in deficient recovery of plantar foot muscles which have been func tionally denervated with botulinum toxin type A, suggesting the importance of serotonin neurons in functional recovery. Recently, we found that neurologic recovery after spinal cord injury was retarded by intracerebroven tricular injection of 5,7-DHT, but not by p chlorophenylalanine or reserpine (17).…”

Section: Discussionmentioning

confidence: 99%

Effect of Thyrotropin-Releasing Hormone(TRH) in Experimental Spinal Cord Injury: A Quantitative Histopathologic Study.

et al. 1991

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Spinal cord injuries in rats were experimentally produced by compress ing the cord (T11 vertebra level) for 60 min with stainless steel screws. Morphometric analysis of the injured cord revealed that at 14 days post-injury, there were significant correlations between the neurologic score (NS) and all morphometric parameters, in cluding total cross-sectional area (rs = 0.438), lesioned area (rs = -0.421) and area of the gray (rs = 0.377) and white matter (rs = 0.704). Although rats treated with thyrotropin-releasing hormone (TRH; 22.5 mg/kg, s.c., twice daily for 7 days starting 24 hr post-injury) showed significant improvement in NS 14 days post-injury, there were no significant differences in morphometric parameters between saline and TRH-treated rats. In addition, no significant correlation was observed between NS and any of the morphometric parameters in TRH-treated rats, even though there was a significant correlation between the area of white matter and NS in saline-treated rats. These results suggest that neurologic recovery closely reflects the histopathologi cal changes evident at the injury site in the present model, and that the improvement of neurologic status seen in rats with cord injury given TRH starting 24 hr post-injury is not due to protection against progression of neural damage at the injury site.Thyrotropin-releasing hormone (TRH) was first reported by Faden et al.(1) to be effec tive in improving the neurologic outcome in an experimental spinal cord injury model in cats. Recently, an ameliorating effect of TRH was also reported in patients with both chronic and stable spinal cord injury (2). TRH has therefore been receiving a great deal of atten tion because of its possible use as a pharma cotherapeutic agent for spinal cord injury. Although the leading model of experimental spinal cord injury is the weight-drop method designed by Allen (3), Faden et al. (4,5) failed to find any direct action of TRH on histo pathological outcome using this model; and more recently, they concluded that this was due to the relatively poor correlation between light-microscopic histological changes and motor recovery, especially with regard to pharmacological changes (6). Recently, we re ported a new model of spinal cord injury in rats using a screw (7), which could be pre pared more easily than the apparatus used in Allen's method. Using this model, we con firmed the dose-dependent accelerating effect of TRH on neurologic recovery when adminis tered for 7 days starting 24 hr after injury, and demonstrated the usefulness of this model (8).

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Spinal cord TRH deficiency is associated with incomplete recovery of denervated muscle in the rat

Cited by 22 publications

References 0 publications

Calcitonin Gene‐related Peptide (CGRP)‐like Immunoreactivity and CGRP mRNA in Rat Spinal Cord Motoneurons after Different Types of Lesions

Calcitonin Gene‐related Peptide (CGRP)‐like Immunoreactivity and CGRP mRNA in Rat Spinal Cord Motoneurons after Different Types of Lesions

The serotoninergic bulbospinal system and brainstern‐spinal cord content of serotonin‐, TRH‐, and substance P‐like immunoreactivity in the aged rat with special reference to the spinal cord motor nucleus

Effect of Thyrotropin-Releasing Hormone(TRH) in Experimental Spinal Cord Injury: A Quantitative Histopathologic Study.

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