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10-24-2008, 12:16 PM | #1 | |||
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In Remembrance
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It has been approved for diabetes for a couple of years, so your doc could prescribe it tomorrow.
1: J Neurol Sci. 2008 Aug 15;271(1-2):131-6. Epub 2008 May 27. The CRF-like peptide urocortin produces a long-lasting recovery in rats made hemiparkinsonian by 6-hydroxydopamine or lipopolysaccharide. Abuirmeileh A, Harkavyi A, Kingsbury A, Lever R, Whitton PS. Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK. We have recently observed that the corticotropin releasing factor related peptide urocortin (UCN) reverses key features of nigrostriatal neurodegeneration following intracerebral injection of either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS). To determine the potential therapeutic utility of UCN here we have studied whether these effects are sustained for several weeks following peptide injection. In addition we have studied whether UCN still shows efficacy in rats with more pronounced nigrostriatal lesions. Rats were lesioned using 6-OHDA or LPS and injected with UCN either 7 or 14 days later. At different time points animals were tested for rotational behaviour (apomorphine, 0.5 mg/kg) and subsequently implanted with bilateral dialysis probes into the striata. The following day rats were dialysed to estimate extracellular striatal dopamine (DA) and then sacrificed for estimation of striatal tissue DA and subsequent immunohistochemistry of TH(+) cells in the substantia nigra (SN). Toxin treated rats given UCN 7 days later showed clear evidence of reduced nigrostriatal damage both 28 and 84 days following UCN compared with saline injection. In rats given UCN 14 days after toxin injection, by which time deficits were maximal, a restoration of nigrostriatal damage was observed. This suggests that UCN is able to elicit a sustained restoration of functional nigrostriatal integrity and has the ability to produce a recovery in severely lesioned rats. These findings suggest that stimulation of CRF (probably CRF(1)) receptors could have therapeutic utility in PD. PMID: 18508084 [PubMed - in process]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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10-24-2008, 12:35 PM | #2 | |||
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Member
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can someone do a rough translation? Sounds like someone has tripped over a piece of potentially life altering information...but I cannot tell for sure. If so, it could get buried in a hurry by those who would prefer it not further undermine the american economy, heal the sick or raise the dead. A job for the NT research team....not me, I'm strictly a philosopher/cheerleader type with a rather jaded outlook.
I'll be watching this thread to see what happens next.
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I would never die for my beliefs because I might be wrong. Bertrand Russell |
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10-24-2008, 02:11 PM | #3 | |||
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In Remembrance
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1: J Neuroinflammation. 2007 Jul 21;4:19.
Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease. Abuirmeileh A, Harkavyi A, Lever R, Biggs CS, Whitton PS. Department of Pharmacology, The School of Pharmacy, London, UK. amjad.abuirmeileh@pharmacy.ac.uk <amjad.abuirmeileh@pharmacy.ac.uk> We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist alpha-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD. PMCID: PMC1976313 PMID: 17659087 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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10-24-2008, 02:15 PM | #4 | |||
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In Remembrance
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1: J Neurosci Res. 2008 Feb 1;86(2):326-38.
Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease. Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L. NeuroNova AB, Stockholm, Sweden. We investigated the effects of exendin-4 on neural stem/progenitor cells in the subventricular zone of the adult rodent brain and its functional effects in an animal model of Parkinson's disease. Our results showed expression of GLP-1 receptor mRNA or protein in the subventricular zone and cultured neural stem/progenitor cells isolated from this region. In vitro, exendin-4 increased the number of neural stem/progenitor cells, and the number of cells expressing the neuronal markers microtubule-associated protein 2, beta-III-tubulin, and neuron-specific enolase. When exendin-4 was given intraperitoneally to naïve rodents together with bromodeoxyuridine, a marker for DNA synthesis, both the number of bromodeoxyuridine-positive cells and the number of neuronal precursor cells expressing doublecortin were increased. Exendin-4 was tested in the 6-hydroxydopamine model of Parkinson's disease to investigate its possible functional effects in an animal model with neuronal loss. After unilateral lesion and a 5-week stabilization period, the rats were treated for 3 weeks with exendin-4. We found a reduction of amphetamine-induced rotations in animals receiving exendin-4 that persisted for several weeks after drug administration had been terminated. Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase- and vesicular monoamine transporter 2-positive neurons in the substantia nigra. In conclusion, our results show that exendin-4 is able to promote adult neurogenesis in vitro and in vivo, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson's disease. (c) 2007 Wiley-Liss, Inc. PMID: 17803225 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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10-24-2008, 02:19 PM | #5 | |||
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In Remembrance
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1: J Neuroinflammation. 2008 May 21;5:19.
Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK. alexander.harkavyi@pharmacy.ac.uk BACKGROUND: It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. METHODS: Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. RESULTS: EX-4 (0.1 and 0.5 mug/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. CONCLUSION: The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay. PMCID: PMC2426681 PMID: 18492290 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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10-24-2008, 02:29 PM | #6 | |||
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In Remembrance
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I'm still trying to get my mind around this one but I do know-
1) All these and about three more are less than two years old, lot of older diabetes stuff but not PD 2) At least two teams after it with Whitton's in the lead 3) Whitton seems to do good work and has been around awhile, he has written the best review of my favorite hypothesis (bacterial toxins) that I've seen and I know enough on that one to know that he is one sharp fellow. He is not the type to write the last bit of that last abstract lightly.
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. Last edited by reverett123; 10-24-2008 at 03:23 PM. |
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10-25-2008, 08:09 AM | #7 | |||
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In Remembrance
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1: J Pharmacol Exp Ther. 2004 Nov;311(2):427-40. Epub 2004 Aug 5.
Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. Heinrichs SC, Koob GF. The Scripps Research Institute, Department of Neuropharmacology, CVN-7, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Organisms exposed to challenging stimuli that alter the status quo inside or outside of the body are required for survival purposes to generate appropriate coping responses that counteract departures from homeostasis. Identification of an executive control mechanism within the brain capable of coordinating the multitude of endocrine, physiological, and functional coping responses has high utility for understanding the response of the organism to stressor exposure under normal or pathological conditions. The corticotropin-releasing factor (CRF)/urocortin family of neuropeptides and receptors constitutes an affective regulatory system due to the integral role it plays in controlling neural substrates of arousal, emotionality, and aversive processes. In particular, available evidence from pharmacological intervention in multiple species and phenotyping of mutant mice shows that CRF/urocortin systems mediate motor and psychic activation, stimulus avoidance, and threat recognition responses to aversive stimulus exposure. It is suggested that affective regulation is exerted by CRF/urocortin systems within the brain based upon the sensitivity of local brain sites to CRF/urocortin ligand administration and the appearance of hypothalamo-pituitary-adrenocortical activation following stressor exposure. Moreover, these same stress neuropeptides may constitute a mechanism for learning to avoid noxious stimuli by facilitating the formation of so-called emotional memories. A conceptual framework is provided for extrapolation of animal model findings to humans and for viewing CRF/urocortin activation as a continuum measure linking normal and pathological states. PMID: 15297468 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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11-01-2008, 06:53 PM | #8 | ||
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New Member
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Hi and thanks for this hopeful posting . Urocortin 1 sounds much better than anything else currently available . A good chance it can reverse g this dreadful disease, no invasive operations, amd no waiting for trials, right? It certainly is what I've been praying for. So why has the interest here waned?
Maybe because its impossible to get any info on its availability? I can't find any evidence of it being available as a drug/injection, given to diabetics . All I can see is that www dot PhoenixPeptide dot com sell this peptide to researchers. This in itself may be a good lead, if one knew what to do with it. But I don't. So, does anyone have any further information on the actual drug AVAILABLE to diabetics ? If it was a drug sold in Europe I would be able to get it prescription-free from my trusted european pharmacist. Hope someone has an answer .Thanks , Pippa |
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11-01-2008, 08:21 PM | #9 | ||
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Senior Member
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I could not find it either, except for researchers, and even then, there were indications that the peptide available for research comes from bovine brain (no, thanks). I did read somewhere that we make urocortin on our skin, which is interesting, but not particularly helpful.
Also, should note that there are apparently three urocortins, urocortin, urocortin 2, and urocortin 3. All of my research indicated that only urocortin was helpful; indeed, the articles actually said urocortin 2 and 3 had no effect but plain urocortin had siginificant effect. Yes, very hopeful, but how does one get it, and will the plain urocortin cross the BBB? I did not get a clear answer to that particular question, but will continue to see if I can. |
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04-06-2009, 12:54 PM | #10 | |||
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In Remembrance
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The work in progress uses a diabetes drug called Ex-4. Ex-4 is a mimic of a hormone called GLP-1. GLP-1 is produced in the gut but has receptors in the brain as well. The excitement is that stimulating the brain receptors cured the PD rats (RWP, I guess ). Not "slowed progression" nor "relieved symptoms." For the first time it has been claimed "cured."
Normally, GLP-1 is made in the gut and a little makes it into the blood but is supposedly quickly broken down by enzymes and only a little makes it to the brain. The idea is to use enzyme-resistant versions of GLP-1 (Ex-4 being one) to increase what gets to the brain. But it seems to me that if there are other ways to increase the amount of GLP-1 in the blood that that is worth considering. And there are things that do increase it and some of them are already thought helpful in PD. Exercise increases GLP-1 levels, for example. Certain oils do, too. And now it seems that the "Rosebud Low Glycemic Diet" does too. "It's been discovered that eating a meal with a low GI (glycemic index) increases gut hormone production, which leads in turn to suppression of appetite and the feeling of fullness. This new research was presented at the annual Society for Endocrinology meeting in the U.K." from http://shamvswham.blogspot.com/2009_03_01_archive.html We already know that PWP have glycemic issues, that Ldopa makes them worse, and that some researchers suspect Alzheimer's to be a glycemic problem too. And we know that GLP-1 is a potent player in the production of insulin. Coincidence?
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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