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)

ACTH peptide fragments demonstrate potent neurotrophic effects on peripheral nerves in situ, central neurons in culture, and have been implicated to have effects on central neurons in vivo. Neurotoxic lesioning of the nigrostriatal system, which depletes the striatum of dopamine, provides a feasible model of central regeneration in which to test these peptides. Male Sprague-Dawley rats were lesioned unilaterally with 6-hydroxydopamine (8 micrograms/4 microliters), infused into the substantia nigra. They were subsequently treated with 10 micrograms/kg IP of Org 2766 [ACTH/MSH(4-9) analogue] or saline every 24 h starting immediately after the infusion and were observed for 2 weeks. Rotational behavior data indicate that Org 2766 significantly decreases ipsiversive turning (p < 0.05), induced by amphetamine (2 mg/kg), as well as accelerating the onset of denervation supersensitivity induced by apomorphine (0.05 mg/kg). Evaluation of dopamine immunohistochemistry, using an anti-tyrosine hydroxylase antibody, demonstrates an enhanced intensity of staining in the ORG 2766-treated tissue compared to its saline counterpart. This difference is confirmed and quantified through specific high-affinity dopamine uptake. Dopamine uptake is about 17% higher in the striata of animals treated with Org 2766. Higher dopamine uptake levels in these ACTH-treated animals correlate with greater fiber density in this group. Therefore, it appears that treatment with the ACTH/MSH(4-9) analogue Org 2766 (10 micrograms/kg/24 h) offers a protective effect from 6-OHDA lesions in the substantia nigra as well as accelerating various compensatory mechanisms involved in functional recovery.
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PMID:Rapid neurotrophic actions of an ACTH/MSH(4-9) analogue after nigrostriatal 6-OHDA lesioning. 790 91

In studies on aged and brain-lesioned rats the chronic administration of the ACTH(4-9) analog Org2766 has been demonstrated to improve the behavioral performance. Those results suggest that maintenance of hippocampal functioning in senescence and facilitation of functional recovery after brain damage are not due to facilitated reinnervation of denervated structures as suggested in previous studies concerning regeneration of the PNS. Alternative explanations may refer to either the neuroprotective properties of the peptide as demonstrated when chronic treatment immediately follows the damage, or a peptide-induced general change in attention that indirectly may contribute to functional recovery. The behavioral effects after acute treatment with ACTH-like peptides have been previously associated with sustained attention by enhanced neuronal excitability of limbic structures. Now, a hypothesis accounting for both neuroprotection and enhanced attention is forwarded by supposing that the peptide exerts its influence by modulation of NMDA receptor activation. Therefore, the acute effects and interactions between the peptide and the NMDA receptor antagonist AP5 (D,L-2-amino-5-phosphonopentanoic acid), and the peptide and NMDA were studied in a water maze and an open field. Impaired water maze performance induced by an acute intracerebroventricular administration of AP5 was counteracted by the ACTH(4-9) analog Org2766, whereas the peptide alone did not affect spatial orientation. NMDA induced extreme locomotor activity at the periphery of the open field. Interestingly, the ACTH(4-9) analog strongly suppressed NMDA-induced enhanced locomotor activity and normalized the pattern of exploratory behavior.
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PMID:The ACTH(4-9) analog Org2766 modulates the behavioral changes induced by NMDA and the NMDA receptor antagonist AP5. 791 Feb 5

Short peptide sequences of ACTH 1-39 (the ACTH 4-9 analog Org 2766, ACTH 4-10 and its analog BIM 22015, and ACTH 1-13 [alpha-MSH]), which do not stimulate the adrenal cortex, have profound effects on the developing and regenerating neuromuscular system, in neonatal and in adult rats. Both development and regeneration are accelerated, as indicated by improved morphological, electrophysiological, behavioral and biochemical parameters. Regeneration in the central nervous system is problematic but the ACTH peptides may provide protection for CNS neurons, enhance denervation sensitivity or permit compensatory processes which facilitate functional recovery. Neuronal cells in culture respond to ACTH peptides by greater neurite outgrowth, and in some cell types, by increased B-50 expression. In all cases, susceptibility to ACTH peptide treatment varies with cell type, age, the specific peptide administered, its dosage and pattern of administration. External stress and the gender of the animal are additional factors that interact with the neurotrophic actions of the melanocortins.
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PMID:Non-corticotropic ACTH peptides modulate nerve development and regeneration. 827 76

1. The systemic absorption and the neurotrophic effect of the metabolically stabilized ACTH (4-9) analogue, Org2766, were investigated following intranasal (i.n.) administration. 2. Without additives the nasal bioavailability of the peptide was in the order of 15 and 10% in rats and rabbits, respectively. The absorption could be improved by addition of a variety of absorption enhancers to the nasal preparation. The beta-cyclodextrin derivative, dimethyl-beta-cyclodextrin (DM beta CD) at a concentration of 5% (w/v) improved the absorption in rats about 5 fold from 13 +/- 4% (mean +/- s.d.) for administration of the peptide alone to 65 +/- 21%, and in rabbits 1 to 2 fold, from 10 +/- 6% to 17 +/- 8%. 3. The increased permeability of the rat nasal mucosa for Org2766 caused by DM beta CD in rats reversed substantially within 1 h. However, the nasal absorption had not yet completely returned to the level without enhancer. 4. S.c. administered Org2766 accelerated the functional recovery from peripheral nerve damage in rats. However, the peptide did not facilitate nerve repair following i.n. administration with DM beta CD, in spite of the fact that Org2766 was well absorbed. I.v. injection of Org2766 was also ineffective.
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PMID:Nasal administration of an ACTH(4-9) peptide analogue with dimethyl-beta-cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics. 830 72

The ACTH(4-9) analog ORG2766 has been known to affect recovery of damaged functions resulting from injury to neural tissue. The peptides efficacy has often been ascribed to a facilitation of existing recovery, and immediate treatment seemed a prerequisite for efficacy. However, various results in other recovery paradigms do not refer to the neurotrophic properties of the peptide, but rather ascribe the effectiveness of ORG2766 to a general change in attention that indirectly affects functional recovery. Such a change in state is theoretically independent of the occurrence of spontaneous recovery, and, thus, treatment would not be required to coincide with recovery immediately after the damage. To see if ORG2766 can influence the recovery of function without the simultaneous occurrence of spontaneous recovery, this study employed a delay of 7 months after the occurrence of a fimbria lesion before ORG2766 was administered. The selective fimbria lesion produced an impairment in Morris maze performance, which could be attenuated by chronic treatment with ORG2766 immediately after the lesion as well as after 7 months. With respect to spatial orientation, no improvement is assessed in untreated lesioned rats, as the impairment of Morris maze performance in untreated fimbria-lesioned rats is as severe as right after the lesion. The data indicates that efficacy of the ACTH(4-9) analog does not rely on the acceleration of spontaneous recovery processes in this paradigm. The behavioral effects of ORG2766 are discussed in the context of a peptide-induced state of enhanced attention.
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PMID:ACTH(4-9) analog ORG2766 treatment 7 months delayed still improves morris maze performance of fimbria-lesioned rats. 884 46

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis size was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.
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PMID:X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients. 1093 Nov 8

It has been shown that alphaMSH and the nonmelanotropic ACTH/MSH(4-9) analog ORG 2766 can ameliorate cisplatin-induced neurotoxicity and ototoxicity. Here, we investigated whether these peptides delay the occurrence of the cisplatin-induced shift in auditory threshold, and whether they affect the subsequent recovery of cochlear potentials. Chronically implanted round window electrodes were used to obtain daily recordings of auditory nerve compound action potentials (CAP) and cochlear microphonics at frequencies ranging from 2 to 16 kHz. Cisplatin (1.5 mg/kg i.p.) plus alphaMSH, ORG 2766 (75 mug/kg s.c.), or saline were injected daily until the 40-dB CAP threshold shift at 8 kHz was reached. Endocochlear potential (EP) was measured either 1-2 days or 28 days later, followed by morphometric analysis of the cochlea. Peptide cotreatment did not consistently delay the threshold shift; however, the CAP threshold recovered faster and to a greater extent, with the potency order being alphaMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the alphaMSH-treated animals only. CAP amplitude at high sound pressures, which depends more on nerve function than on outer hair cell (OHC) function, decreased severely in all groups but recovered significantly in the alphaMSH- and completely in the ORG-2766-cotreated group. EP was significantly lower in the first days after the threshold shift but had completely recovered at 28 days. Morphometric analysis of the spiral ganglion also indicated involvement of ganglion cells. OHC loss was most severe in the basal turn of saline-cotreated animals. These data suggest that the cisplatin-induced acute threshold shift might be due to reversible strial failure, whereas subsequent OHC survival determines the final degree of functional recovery. Both OHC loss and neuronal function were ameliorated by peptide cotreatment.
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PMID:Cisplatin ototoxicity involves organ of Corti, stria vascularis and spiral ganglion: modulation by alphaMSH and ORG 2766. 1456 1

A quantitative analysis of zone-specific proliferation was done to determine the recovery of adrenal cortical zonation during regeneration after enucleation. Adult male rats underwent adrenal enucleation [unilateral enucleation (ULE)] or sham surgery, both accompanied by contralateral adrenalectomy. At 2, 5, 10, and 28 days, blood and adrenals were collected to assess functional recovery. Adrenal sections were immunostained for Ki67 (proliferation), cytochrome P-450 aldosterone synthase (P-450aldo, glomerulosa), and cytochrome P-450 11beta-hydroxylase (P-45011beta, fasciculata). Unbiased stereology was used to count proliferating glomerulosa and fasciculata cells. Recovery of fasciculata secretory function occurred by 28 days as reflected by plasma ACTH and corticosterone, whereas glomerulosa function reflected by plasma aldosterone remained low at 28 days. At 5 days, ULE adrenals showed increased Ki67+ cells in the glomerulosa and inner fasciculata, whereas at 10 and 28 days increased proliferation was restricted to the outer fasciculata. These data show that enucleation results in transient elevations in glomerulosa and inner fasciculata cell proliferation followed by a delayed increase in the outer fasciculata. To assess adrenal growth in enucleated adrenals previously suppressed by the presence of an intact adrenal, rats underwent ULE and sham surgery; after 4 wk, the intact adrenal was removed and enucleated adrenals were collected at 2, 5, and 10 days. Overall, proliferation was delayed in this model, but at 5 days, Ki67+ cells increased in the outer fasciculata, whereas by 10 days, increased proliferation occurred in the outer and inner fasciculata. The key novel finding of increased proliferation in the inner fasciculata suggests that the delayed growth of the enucleated adrenal results in part from a regenerative response.
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PMID:Zone-specific cell proliferation during adrenocortical regeneration after enucleation in rats. 1597 74

Adrenalectomy continues to play an important role in the management of Cushing's syndrome (CS). Untreated CS causes considerable physical and mental morbidity and mortality. However, little information is available on the effect of adrenalectomy in ameliorating functional disabilities in CS patients. Our study assesses the long-term outcome of adrenalectomy in patients with CS. This is a retrospective analysis of CS patients managed during 1990-2005 at a tertiary care center. We analyzed the clinical presentation, endocrine evaluation, and surgical management preoperatively and following adrenalectomy. The subjects were 37 patients with CS (age 24.5 +/- 15 years, range 1-60 years; male:female 1.0:1.2). There were various etiologies--unilateral adrenocortical adenoma (n = 11), adrenocortical carcinoma (n = 13), pituitary ACTH-secreting adenoma with failed transsphenoidal surgery (n = 4), ectopic unidentified ACTH source (n = 7), bilateral adrenal macronodular hyperplasia (n = 1), primary pigmented nodular adrenal hyperplasia (n = 1) --for which the patients underwent adrenalectomy: unilateral (n = 22), bilateral (n = 13), or adrenonephrectomy (n = 2). Two patients died during the perioperative period owing to chest infection and sepsis. At the median follow-up of 60 months (range 6-144 months), the patients exhibit significant persistence of obesity (41%), proximal muscle weakness (44%), menstrual irregularity (8%), hypertension (31%), and insulin-dependent diabetes (29%). Hirsutism and psychological abnormalities persisted to a lesser extent. All patients had biochemical cure of CS following surgery evidenced by the 8 a.m. basal cortisol < or = 5 microg/dl. The hypothalamic-pituitary-adrenal axis recovered as shown by normalization of the short synacthen-stimulated cortisol level (peak level > or = 20 microg/dl) after a median follow-up of 9 months (range 6-18 months). Incomplete clinical recovery following adrenalectomy emphasizes the need of early recognition and prompt treatment of CS. Surgery for adrenocortical adenoma is safe and effective; however, survival of patients with CS due to adrenocortical carcinoma remains poor. Bilateral adrenalectomy provides early control of hypercortisolism in selected cases of unlocalized ectopic ACTH syndrome or failed transsphenoidal surgery. Even though functional recovery is incomplete after adrenalectomy, quality of life improves considerably.
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PMID:Outcome of adrenalectomy for Cushing's syndrome: experience from a tertiary care center. 1753 56

Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of circulatory shock, myocardial ischemia, ischemic stroke, traumatic brain injury, respiratory arrest, renal ischemia, intestinal ischemia and testicular ischemia, as well as in experimental heart transplantation. Moreover, melanocortins improve functional recovery and stimulate neurogenesis in experimental models of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediated by brain melanocortin MC(3)/MC(4) receptors, whose activation triggers protective pathways that counteract the main ischemia/reperfusion-related mechanisms of damage. Induction of signaling pathways and other molecular regulators of neural stem/progenitor cell proliferation, differentiation and integration seems to be the key mechanism of neurogenesis stimulation. Synthesis of stable and highly selective agonists at MC(3) and MC(4) receptors could provide the potential for development of a new class of drugs for a novel approach to management of severe ischemic diseases.
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PMID:Melanocortins as potential therapeutic agents in severe hypoxic conditions. 2253 Nov 39


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