Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. In rats, recovery of sensory-motor function following a crush lesion of the sciatic or tibial nerve was monitored by measuring foot reflex withdrawal from a local noxious stimulation of the foot sole. 2. Putative neurotrophic compounds were tested on this functional recovery model: melanocortins (peptides derived from ACTH (corticotropin) and alpha-MSH (melanotropin], gangliosides and nimodipine were effective whereas isaxonine and TRH (thyrotropin releasing hormone) were not. 3. Structure-activity studies with melanocortins revealed a similar effectiveness of alpha-MSH, [N-Leu4, D-Phe7]-alpha-MSH, desacetyl-alpha-MSH and the ACTH analogue ORG 2766, questioning the validity of the previously suggested notion that the melanotrophic properties of these peptides are responsible for their neurotrophic effect. 4. As recovery of function after peripheral nerve damage follows a similar time course in hypophysectomized (five days post operation) and sham-operated rats, effective melanocortin therapy does not mimic an endogenous peptide signal in the repair process from pituitary origin. 5. Subcutaneous treatment with ORG 2766 (7.5 micrograms kg-1 48 h-1) facilitates recovery of function following peripheral nerve damage in young (6-7 weeks old), mature (5 month old) and old (20 month old) rats. 6. In view of the diversity in structure of the effective neurotrophic factors and the complexity of nerve repair, the present data support the notion that peripheral nerve repair may be facilitated by different humoral factors likely to be active on different aspects of the recovery process.
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PMID:Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat. 167 80

The behavioral effects of two peptides (HOE 427) and ORG 31433) related to the ACTH-(4-9) analog ORG 2766 were investigated in Wistar rats in a number of tests in which Org 2766 is active. Subcutaneous administration of HOE 427 in a dose of 0.5 ng/kg or ORG 31433 in doses of 0.5-5.0 ng/kg facilitated passive avoidance behavior whereas these peptides attenuated the avoidance response in doses of 25 ng/kg and 250 ng/kg respectively. ORG 31433 (0.1 - 1.0 microgram/kg) decreased motor activity of group housed rats tested under low light conditions. Furthermore subcutaneous (1.0- 10.0 ng/kg) or oral (10 microgram/kg) administration of ORG 31433 accelerated functional recovery from 6-hydroxydopamine (6-OHDA)-induced lesions in the nucleus accumbens which cause motor hypoactivity. The experiments show that as compared to ORG 2766 the peptides HOE 427 and ORG 31433 induce qualitatively similar responses but are approximately 10 to 100 times more potent. These data may imply that substitution of the C-terminal COOH group of ORG 2766 yields neuropeptides with increased potency.
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PMID:Structural modifications of the ACTH-(4-9) analog ORG 2766 yields peptides with high biological activity. 184 25

The functional recovery from impaired motor activity induced by 6-hydroxydopamine lesions in rat nucleus accumbens was accelerated by subcutaneous treatment with the ACTH-(4-9) analogue Met/O2/-Glu-His-Phe-D-Lys-Phe (ORG 2766). Treatment was effective after daily injections of ORG 2766 dissolved in saline during the first 6 days following the lesion (ED50: 28.5 ng kg-1 day-1) or after a single injection of the peptide in a biodegradable microsphere formulation administered after the lesion (ED50: 8.9 ng kg-1 day-1). This study shows that a single injection of a microsphere preparation can replace multiple injections with ORG 2766 in order to facilitate functional recovery after brain damage.
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PMID:A single injection of a biodegradable microsphere formulation of the ACTH-(4-9) analogue ORG 2766 accelerates functional recovery after brain damage. 198 Feb 95

Functional recovery from motor hypoactivity of rats with 6-OHDA lesions in the nucleus accumbens is accelerated by intra-accumbal or subcutaneous treatment with the ACTH-(4-9) analog ORG 2766. The spontaneous recovery period of 3 weeks is shortened to 7 days by daily treatment with this peptide during the first 6 days after the lesion. The 6-OHDA lesion induced a decrease of about 30-40% in the levels of dopamine, HVA and DOPAC as well as in the uptake of [3H]dopamine in nucleus accumbens tissue in vitro. Treatment with ORG 2766 during the first 6 days following the lesion did not affect the lesion-induced changes in these biochemical parameters. Binding studies with [3H]haloperidol in nucleus accumbens tissue of placebo or ORG 2766-treated sham-lesioned rats revealed a linear Scatchard plot 7 days after the sham lesion. In tissue of placebo-treated 6-OHDA lesioned animals a similar linear Scatchard plot was found but in tissue of ORG 2766-treated 6-OHDA-lesioned rats the Scatchard plot was curvilinear in shape indicating two types of binding sites. In the 6-OHDA-lesioned rats treated with ORG 2766 the behavioral response upon apomorphine challenge was enhanced suggesting the existence of functional supersensitivity of the DA system. Similar changes in Scatchard plots and apomorphine-induced behavioral changes have been previously reported after spontaneous recovery. The present study indicates that ORG 2766 accelerates the process of functional recovery from impaired motor behavior of rats with 6-OHDA lesions in the nucleus accumbens, which may be due to development of denervation supersensitivity.
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PMID:Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. II. Facilitation by the ACTH-(4-9) analog ORG 2766. 215 93

The functional recovery from impaired motor activity caused by 6-OHDA lesions in the nucleus accumbens is accelerated by the ACTH-related peptides ACTH-(4-10), alpha-MSH (ac-Ser1-ACTH-(1-13)NH2), ACTH-(7-10) and the ACTH-(4-9) analog ORG 2766. The peptides ACTH-(4-7) and Phe-D-Lys-Phe were not effective in this respect. This indicates that this effect of ACTH-derived peptides is located in the 7-10 part of the molecule whereas for the effect of ORG 2766 a bigger part of the molecule may be required. ORG 2766 was effective after intra-accumbal, subcutaneous and oral administration. The differences in potencies between the 3 routes of administration (ED50 0.76 ng/kg, 28.5 ng/kg and 80.6 micrograms/kg, respectively) suggest that the peptide exerts its effect by facilitating recovery processes at the lesion site. Studies with ORG 2766 showed that treatment during the first days following the induction of the lesion is essential for the facilitating action of the peptide on spontaneous recovery from brain damage.
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PMID:Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. III. Further analysis of the facilitating effect of the ACTH-(4-9) analog ORG 2766. 215 94

Rats with 6-OHDA lesions in the nucleus accumbens which were treated intra-accumbally with control serum during the first week following the lesion showed a similar level of motor activity 3 weeks after the lesion as sham-lesioned rats treated with control serum. In 6-OHDA-lesioned rats that were identically treated with antiserum against alpha-MSH or the ACTH-(4-9) analog ORG 2766 motor activity was decreased 3 weeks after the lesion. Intra-accumbal treatment with the antisera did not affect motor activity of sham-lesioned rats. The increased motor activity after apomorphine injection into the nucleus accumbens of control serum-treated 6-OHDA-lesioned rats was not observed in 6-OHDA-lesioned rats treated with the antisera. Furthermore, [3H]haloperidol binding studies showed that the changes in the DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats treated with control serum, which may reflect denervation supersensitivity, were not observed in 6-OHDA-lesioned rats treated with the antisera. The present data indicate that the functional recovery and the concurrent development of supersensitive DA receptor systems in the nucleus accumbens of 6-OHDA-lesioned rats are delayed by intra-accumbal treatment with ORG 2766 or alpha-MSH antiserum. This suggests that endogenous ACTH/MSH-like factors may be mediating the recovery processes.
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PMID:Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. IV. Delay by intra-accumbal treatment with ORG 2766- or alpha-MSH antiserum. 215 96

An injection of streptozocin (STZ) was used to study diabetes-induced peripheral neuropathy in rats. In such rats the values of motor nerve conduction velocity and sensory nerve conduction velocity were decreased compared with the values obtained in nondiabetic controls from 3 wk after STZ injection onward. In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage. This article documents the beneficial effect of the peptide Org 2766, an ACTH-(4-9) analogue, in diabetic peripheral neuropathy. Chronic subcutaneous treatment of diabetic rats with Org 2766 results in a significant enhancement of both motor and sensory nerve conduction velocity compared with saline-treated diabetic rats. Histological analysis of cross sections of the sural nerve showed no difference in the total number of nerve fibers in saline- or peptide-treated diabetic rats. In contrast, a difference in fiber size distribution was demonstrated; i.e., the sural nerves of diabetic rats contained fewer thick myelinated fibers. Treatment with Org 2766 resulted in a normal distribution. Apparently, the peptide Org 2766 has a protective action on nerve fibers and nerve function during STZ-induced diabetes.
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PMID:Beneficial effect of Org 2766 in treatment of peripheral neuropathy in streptozocin-induced diabetic rats. 253 28

The efficacy of melanocortins (alpha-MSH and an ACTH-(4-9) analog, Org.2766) in accelerating functional recovery from sciatic nerve damage following various types of subcutaneous and oral administration was assessed in the rat. Furthermore, the effectiveness of the local delivery of melanocortins to the site of injury was examined. An accelerated recovery was evident following subcutaneous constant delivery of Org.2766 from an osmotic mini-pump and from biodegradable polymere microspheres, and was as effective as repeated subcutaneous injections of alpha-MSH or Org.2766. Oral administration of Org.2766 was ineffective. Local application of Org.2766, achieved by wrapping a peptide-impregnated biodegradable gelatine foam matrix around the site of injury, facilitated recovery as well. The biodegradable microspheres and gelatine foam matrix may be of importance in eventual clinical use as effective vehicles for administration of melanocortins in the treatment of peripheral nerve damage.
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PMID:alpha-MSH and Org.2766 in peripheral nerve regeneration: different routes of delivery. 283 94

The effects of chronic treatment with the ACTH-(4-9) analogue Org 2766, alpha-MSH, and gamma 2-MSH were studied on T-maze reversal learning and on behavior assessed on the basis of open-field and other gross behavioral activities, grasping responses, inspection of various reflexes and electrical footshock sensitivity of rats with parafascicular lesions or sham-lesions. Repeated administration of Org 2766 and alpha-MSH to parafascicular area-lesioned rats resulted in functional recovery of impaired T-maze reversal learning. The structurally related neuropeptide gamma 2-MSH was without any effect. The alpha-MSH effect did not depend on time after lesioning as treatments during the first or second post-operative week were equally effective. Chronic peptide treatments did not change disturbed motor functions of parafascicular-lesioned rats, as measured by open-field activity, other gross behavioral activities and grasping responses. Since acute peptide treatments did not affect the impaired reversal learning performance of lesioned rats, the beneficial effect of Org 2766 and alpha-MSH could not be explained as a short-term effect on attention and motivation. It was more likely to be an accelerated recovery of cognitive function as a result of long-term neurotropic influences.
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PMID:Beneficial effect of chronic treatment with Org 2766 and alpha-MSH on impaired reversal learning of rats with bilateral lesions of the parafascicular area. 299 19

The results of the present study demonstrate that administration of the ACTH-(4-9) analogue Org 2766 acutely enhances behavioral, morphological, and biochemical recovery after nigrostriatal destruction. Animals treated with Org 2766 (10 micrograms/kg every 24 hr) demonstrated an acceleration of denervation supersensitivity and a significantly decreased ipsilateral rotational response, as compared to their saline counterparts. Upon evaluation of the mesolimbic DA system using open field behavior, peptide-treated rats demonstrated a compensatory response in their rearing behavior. Furthermore, tyrosine hydroxylase immunocytochemical analysis indicated an enhanced staining in the Org 2766-treated groups. This evaluation was confirmed and quantified using specific high-affinity dopamine uptake. The brains of animals treated with Org 2766 maintained higher uptake levels, suggesting a greater fiber density than the saline-treated animals. Although recovery via reinnervation is very unlikely in this short period of time, improved recovery may be the result of a protective effect of Org 2766 after administration of 6-OHDA into the substantia nigra. Thus, it appears that Org 2766 provides the rapid effects in this system, by both accelerating some compensatory mechanisms necessary for functional recovery and promoting cell survival by providing neuronal protection. However, it does not appear that this protection is due to NMDA receptor manipulation. Org 2766 neither mimicked the NMDA antagonist MK-801 behaviorally nor biochemically in binding displacement studies. Interestingly, other studies have suggested that only the full ACTH molecule, and fragments larger than ACTH-(1-17), demonstrated binding activity at micromolar concentrations, whereas the shorter, noncorticotropic fragments were either less active or inactive (Table 2). As for ACTH-(4-10) immunoreactivity, it appears that this neurotrophic fragment of ACTH reappears in adults following injury to the nigrostriatal system. In addition, the systemically administered ACTH-(4-9) analogue, Org 2766, seems to be gaining access to the CNS, but is only effective in the injured system. Therefore, based on the immunocytochemical localization of the ACTH-(4-10) fragment in neonatal brains and in the injured adult rat CNS, the interesting possibility may be raised that endogenous ACTH peptides appear during both ontogeny and regeneration. These studies demonstrate once again that biological responses to the family of ACTH/MSH peptides depend on the specific peptide fragment administered, its dosage, and the timing of the administration. Consequently, since early intervention is of vital importance in CNS recovery processes, synergistic administration of ACTH fragments and other neurotrophic agents may offer a viable approach with which to combat degeneration in the CNS.
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PMID:Specificity versus redundancy of melanocortins in nerve regeneration. 783 97


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