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- August 10, 2017 at 11:36 am #2848Pereise1Participant
Hello All, I’m going to be copy + pasting our prior discussions about what possibilities there are for curing Narcolepsy from a scientific viewpoint. A few walls of text to follow:
Okay, so a bit of a sensationalist title, but it’s what we all yearn for right? Unfortunately, because of the capitalistic limits of modern medicine, there sure doesn’t seem to be anything in the pipeline other than tissue transplantation, which is a an invasive crap shoot that might just kill us once and for all with current techniques. So instead of hypotheticals, let’s think as far as what we can do with what we currently know. So the cause is really of no consequence, the damage is done, and we need to get some semblance of functioning again. Granted, a number of other disorders can imitate narcolepsy, but let’s focus on “Damage in the hypothalamus” Narcolepsy.
Now, it’s known that after a traumatic brain injury (TBI) or a stroke, reactive gliosis by glial cells in the brain cause a glial scar to form. Evidence of this happening is detailed in the following studies:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717206/ (Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy)
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-narcolepsy-in-adults/abstract/57 (Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy)
Herein lies the hard part and the reason Narcolepsy is so hard to treat and solve. When a glial scar is formed in the Central Nervous System (CNS) or spinal cord, it forms a lining that resists axon growth. Therefore, without intervention, the scar would be permanent, and no amount of neurogenesis inducing substances would be able to penetrate the glial scar. However, research in this field has accelerated highly in recent years, and there is hope.
The brain uses different growth factors such as BDNF, NGF, GDNF, NT3, and CNTF to extend dendritic branching and axons. The goal is to use these to grow new orexin neurons over the scar tissue in the hypothalamus, and/or convert the glial cells into functioning neurons. The glial scar has a number of ways that it inhibits growth. It’s a little too complicated to go into too much detail, but I’ll include a few main ones as well as links to a number of studies at the bottom.
1. Modification of sulphated proteoglycans
What are these you may ask? I’m going to quote extensively from the study “Regeneration Beyond The Glial Scar” (http://www.nature.com/nrn/journal/v5/n2/full/nrn1326.html). To start:
In addition to growth-promoting molecules46, 47, astrocytes produce a class of molecules known as proteoglycans48, 49. These ECM molecules consist of a protein core linked by four sugar moieties to a sulphated GLYCOSAMINOGLYCAN (GAG) chain that contains repeating disaccharide units. Astrocytes produce four classes of proteoglycan; heparan sulphate proteoglycan (HSPG), dermatan sulphate proteoglycan (DSPG), keratan sulphate proteoglycan (KSPG) and chondroitin sulphate proteoglycan (CSPG)50. The CSPGs form a relatively large family, which includes aggrecan, brevican, neurocan, NG2, phosphacan (sometimes classed as a KSPG) and versican, all of which have chondroitin sulphate side chains. They differ in the protein core, as well as the number, length and pattern of sulphation of the side chains51, 52, 53. Expression of these CSPGs increases in the glial scar in the brain and spinal cord of mature animals54, 55, 56.
Proteoglycans have been implicated as barriers to CNS axon extension in the developing roof plate of the spinal cord57, 58, in the midline of the rhombencephalon and mesencephalon59, 60, at the dorsal root entry zone (DREZ)61, in retinal pattern development62, 63, and at the optic chiasm and distal optic tract64, 65. Extensive work has demonstrated that CSPGs are extremely inhibitory to axon outgrowth in culture. Neurites growing on alternating stripes of laminin and laminin/aggrecan had robust outgrowth on laminin, but at the sharp interface between the two surfaces, growth cones rapidly turned away (unlike their stalled behaviour in a gradient, see above). The inhibitory nature of the proteoglycan-containing lanes can repel embryonic as well as adult axons, and the effect can last for more than a week in vitro. The turning behaviour is not usually mediated by collapse of the entire growth cone, but rather by selective retraction of FILOPODIA in contact with CSPG and enhanced motility of those on laminin66, 67. CSPGs are potent inhibitors of a wide variety of other growth-promoting molecules, including fibronectin and L1 (Refs 68,69).
This is one of the most important steps to overcome. In the same study, it has been shown that, and I quote, “chondroitinase — an enzyme extracted from the bacterium Proteus vulgaris that selectively removes a large portion of the CSPG GAG side chain and renders CSPGs less inhibitory”. Now, unfortunately I don’t know where to get chondroitinase, if it passes the BBB, or how to guide it to the hypothalamus. However, after scouring pubmed for hours to find a replacement, I found good ol’ Turmeric helps here:
Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar
We found that cur inhibited the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and NF-κb; reduced the expression of the intracellular components glial fibrillary acidic protein through anti-inflammation; and suppressed the reactive gliosis. Also, cur inhibited the generation of TGF-β1, TGF-β2, and SOX-9; decreased the deposition of chondroitin sulfate proteoglycan by inhibiting the transforming growth factors and transcription factor; and improved the microenvironment for nerve growth. Through the joint inhibition of the intracellular and extracellular components of glial scar, cur significantly reduced glial scar volume and improved the Basso, Beattie, and Bresnahan locomotor rating and axon growth.
Turmeric also has HDAC inhibiting properties, making the brain more malleable to change and encouraging it to return to homeostasis. I won’t go too deep into HDAC but it seems to help.
2. Blocking the effects of myelin
Again, what’s this and what would it do? Here’s another citation from the same article:
In addition to enhancing regeneration by removing the inhibitory effects of CSPGs, extensive work has shown that blocking Nogo, a myelin-associated inhibitor of regeneration, improves regeneration105. Antibodies directed against the Nogo receptor administered into spinal cord lesion sites106 or even systemically107 seem to enhance regeneration, although recent work108 has disputed whether this is truly enhanced regeneration or merely local sprouting. Indeed, it is now being suggested that most of the functional recovery that is seen when inhibitors of myelin are used occurs as a result of remodelling of local circuits, such that functional recovery is mediated along uninjured long axons108. This proposal, in conjunction with work from our laboratory demonstrating rapid axon regrowth from adult neurons in the presence of degenerating white matter83, 84, as well as the differences between growth cone collapse and dystrophy, indicates that myelin might not be acting fundamentally to inhibit long-distance regeneration. In fact, it has even been suggested that myelin might facilitate axon growth under certain conditions109.
So how do we get around this issue? Here, we turn to Longecity and the amazing research of some of users there (http://www.longecity.org/forum/topic/62431-nogo-a-inhibition-and-brain-regrowth/#entry737252). To cite only 2 studies, Ginseng and Horny Goat Weed (Icariin) are potent in this regard:
We determined 1) GTS (Ginsenoides) (5-80 mg/kg) treatment after a TBI improved the recovery of neurological functions, including learning and memory, and reduced cell loss in the hippocampal area. The effects of GTS at 20, 40, 60, and 80 mg/kg were better than the effects of GTS at 5 and 10 mg/kg. 2) GTS treatment (20 mg/kg) after a TBI increased the expression of NGF, GDNF and NCAM, inhibited the expression of Nogo-A, Nogo-B, TN-C, and increased the number of BrdU/nestin positive NSCs in the hippocampal formation.
Icariin, the major active component of Chinese medicinal herb epimedium brevicornum maxim, is used widely in traditional Chinese medicine for the treatment of neurological diseases. However, the effects of icariin on myelin inhibitory factors are as yet unclear. In the present study, administration of icariin at 20 mg/kg showed a marked reduction in neurological deficit of middle cerebral artery occlusion rats. Icariin exhibited better inhibitory effects on myelin inhibitory factors: Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein in ischemia regions of middle cerebral artery occlusion rats compared with monosialotetrahexosylganglioside. These results indicate that icariin exhibits potent inhibitory effects on expression of myelin inhibitors after middle cerebral artery occlusion-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein activation, followed by the enhancement of axonal sprouting and regeneration, resulting in neurological functional…
Seems Nogo is among the easier things to inhibit, thankfully.
3. Enhancing the intrinsic growth machinery.
This is pretty straightforward, we want the best environment for these new axons to differentiate and turn into full neurons:
Removal of extrinsic inhibitory cues from the glial scar with treatments such as chondroitinase might aid regeneration, but this might not be sufficient for long-range re-growth. Neurotrophin 3 (NT3) or nerve growth factor (NGF), when delivered directly to transected neurons in the dorsal columns of animals treated with peripheral nerve graft transplants, enhances growth into the graft, out the opposite end and beyond the glial scar into host tissue110, 111. Exogenous NGF administration also induces sprouting into the lesion of crushed dorsal columns112. Intrathecal or adenoviral application of NT3 or NGF to the injured DREZ induces DRG neurons to cross the peripheral nervous system/CNS barrier and penetrate some distance into the spinal cord113, 114, 115, 116, 117, where the regenerating fibres restore nocioceptive function. So, evidence from the injured spinal cord and DREZ indicates that regenerating axons can overcome proteoglycan barriers after neurotrophin stimulation, perhaps through induction of growth enhancing genes, offering an additional therapeutic strategy.
As for Nerve Growth Factor, there’s myriad things that stimulate this, so whatever you decide to take, make sure you enhance it with Acetyl L-Carnitine, which is supposed to enhance NGF by x100 according to a study I’ve recently misplaced. As for Neurotrophin 3, again, we have some amazing phytoconstituents to help. Another Longecity thread (http://www.longecity.org/forum/topic/82911-transforming-glial-cells-into-neurons/) helped me find studies for 2 substances in particular, Chinese Skullcap and Ziziphus Jujube:
Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression.
Signal transducer and activator of transcription 3 (stat3) and basic helix-loop-helix (bHLH) gene family are important cellular signal molecules for the regulation of cell fate decision and neuronal differentiation of neural stem/progenitor cells (NPCs). In the present study, we investigated the effects of baicalin, a flavonoid compound isolated from Scutellaria baicalensis G, on regulating phosphorylation of stat3 and expression of bHLH family proteins and promoting neuronal differentiation of NPCs. Embryonic NPCs from the cortex of E15-16 rats were treated with baicalin (2, 20 μM) for 2h and 7 days. Neuronal and glial differentiations were identified with mature neuronal marker microtubule associated protein (MAP-2) and glial marker Glial fibrillary acidic protein (GFAP) immunostaining fluorescent microscopy respectively. Phosphorylation of stat3 (p-stat3) and expressions of bHLH family genes including Mash1, Hes1 and NeuroD1 were detected with immunofluorescent microscopy and Western blot analysis. The results revealed that baicalin treatment increased the percentages of MAP-2 positive staining cells and decreased GFAP staining cells. Meanwhile, baicalin treatment down-regulated the expression of p-stat3 and Hes1, but up-regulated the expressions of NeuroD1 and Mash1. Those results indicate that baicalin can promote the neural differentiation but inhibit glial formation and its neurogenesis-promoting effects are associated with the modulations of stat3 and bHLH genes in neural stem/progenitor cells.
The treatment with jujube water extract stimulated the expressions of neurotrophic factors in a dose-dependent manner, with the highest induction of ~100% for NGF, 100% for brain-derived neurotrophic factor (BDNF), 100% for glial cell line-derived neurotrophic factor (GDNF) and 50% for neurotrophin 3 (NT3). These results supported the neurotrophic role of jujube on the brain.
Now, I have no idea how long it would take, under ideal circumstances, for the brain to regrow orexin neurons after disinhibiting growth and inducing axon growth in this manner. Any help understanding the process behind regrowing the hypothalamus and guiding growth to this section of the brain would be much appreciated. In the meantime, I leave everyone with some studies:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693386/ (Glial inhibition of CNS axon regeneration)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140701/ (Enhancing Central Nervous System Repair-The Challenges)
http://www.nature.com/nrn/journal/v5/n2/full/nrn1326.html (Regeneration Beyond The Glial Scar)
Also, these longecity threads helped me find a few relevant studies as well as substances to help neurogenesis:
http://www.longecity.org/forum/topic/72296-regenerating-prefrontal-cortex-possible/#entry735916August 10, 2017 at 11:37 am #2850Pereise1Participant
Continuing with our prior discussions:
On 4/7/2017 at 4:37 PM, Ferret said:
All very very interesting. But, since the hypocretin neurons have been destroyed by an auto immune response, what is the point of trying to regenerate new ones when the new ones are going to be destroyed as well. Catch 22.
I wouldn’t say that it’s a sure thing the new neurons would be destroyed. If so, we wouldn’t have autopsies of people in their 50s and 60s with only 30-50% of their orexin neurons destroyed. I’m not sure how it developed in your case Ferret, but I can definitely trace my narcolepsy symptoms appearing shortly after getting the flu, and worsening every 2 years, curiously right after getting sick. From the narcolepsy cases that started coming up after the H1N1 vaccine, it seems that it’s possible for a flu to confuse your body into attacking itself on occasion as opposed to a continuous and constant destruction of orexin neurons. We only have so many.
And if it’s possible to better symptoms, why not? The chronic inflammation involved in Narcolepsy is a factor of many of the negative symptoms as well. Check out this study done on Japanese PWN:
Hum Immunol. 2014 Aug;75(8):940-4. doi: 10.1016/j.humimm.2014.06.023. Epub 2014 Jun 30.
Increased plasma IL-6, IL-8, TNF-alpha, and G-CSF in Japanese narcolepsy.
Narcolepsy is a chronic hypersomnia involving excessive daytime sleepiness and cataplexy. Some susceptibility genes and environmental factors suggest that post-infectious immunological alterations underlie its pathophysiology. To investigate the immunological alterations in narcolepsy patients, we examined cytokines. Nine healthy controls and twenty-one narcolepsy patients with cataplexy were studied. All subjects were positive for the HLA-DRB1(∗)1501-DQB1(∗)0602 allele. Age-, sex-, and body mass index -matched healthy controls were selected. Plasma samples were separated using EDTA-2K-coated blood collection tubes. Bioplex Pro Human Cytokine 17-Plex Assays were used to measure plasma cytokines. Elevations of interleukin (IL)-6, IL-8, granulocyte- colony stimulating factor (G-CSF), and tumor necrosis factor-alpha were found in the narcolepsy group compared with healthy controls (p<0.05). G-CSF values were significantly correlated with the disease duration in narcolepsy patients (r=0.426, p<0.05). IL-8 and G-CSF play major roles in neutrophil activation in respiratory diseases. Since environmental factors including infection are reportedly associated with narcolepsy onset, elevated IL-8 and G-CSF may be involved in the pathophysiology of narcolepsy.
Naturally, anyone with a consistent inflammatory response 24hrs a day would feel like crap. What’s more, several inflammatory cytokines induce sleepiness as well:
Curr Pharm Des. 2008; 14(32): 3408–3416.
The Role of Cytokines in Sleep Regulation
Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions. Additional cytokines are also likely involved but evidence is insufficient to conclude that they are sleep regulatory substances. Many of the symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, can be elicited by injection of exogenous IL1 or TNF. We propose that ATP, released during neurotransmission, acting via purine P2 receptors on glia releases IL1 and TNF. This mechanism may provide the means by which the brain keeps track of prior usage history. IL1 and TNF in turn act on neurons to change their intrinsic properties and thereby change input-output properties (i.e. state shift) of the local network involved. Direct evidence indicates that cortical columns oscillate between states, one of which shares properties with organism sleep. We conclude that sleep is a local use-dependent process influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.
At least trying to neutralize the constant inflammation put out by the glial scar in the hopes of regenerating it would help lower inflammation and theoretically, help with the fatigue. I know I personally discover every time I get sick that it somehow is possible to feel even worse, and I’m willing to bet it’s because of the inflammatory response to being sick.August 10, 2017 at 11:49 am #2851Pereise1Participant
Posted April 18 • Report post
So it seems that the Sigma receptors have a role in hypothalamic neurogenesis. This I got from the following studies:
J Psychopharmacol. 2013 Oct;27(10):930-9. doi: 10.1177/0269881113497614. Epub 2013 Jul 17.
Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.
The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.
Now, I looked long and hard and it seems basically impossible to get out of Europe. However, interestingly enough, it seems Desoxyn (Methamphetamine) raises Orexin while Dextroamphetamine does not. Methamphetamine, interestingly enough, is also a Sigma agonist:
Psychiatry Res. 2016 May 30;239:9-11. doi: 10.1016/j.psychres.2016.02.059. Epub 2016 Feb 27.
Orexin-A level elevation in recently abstinent male methamphetamine abusers.
Research has suggested that methamphetamine (METH) use influences orexin regulation. We examined the difference in orexin-A levels between METH abusers and healthy controls. Fasting serum orexin-A levels were measured in 35 participants who used METH in the preceding 3 weeks and 36 healthy controls. We found METH abusers had significantly higher orexin-A levels. No association was observed between orexin-A levels and METH use variables. Our results, consistent with prior preclinical evidence, showed that recent METH exposure is associated with increased orexin-A expression. Further investigation is required to determine whether orexin-A levels normalize after a longer term of abstinence.
I’m not quite sure what the implications of this would be. In the study “Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system” (https://www.ncbi.nlm.nih.gov/pubmed/10771347), they did find Sigma receptors in the following places:
Diencephalon. Behind the olfactory bulb, the most intense immunostainings were detected in the hypothalamus (Fig. 6). Here, intense immunostaining was associated with perikarya of various sizes and with processes that were dispersed throughout the whole hypothalamus. In all of the brains examined, the highest staining intensities were associated with cells located in the supraoptic (Fig. 6A), the paraventricular (Fig. 6B), the arcuate (Fig. 6C) and the periventricular nuclei. In the thalamus, moderate to intense immunostaining was only detected in cells located in the habenula and the reticular nucleus, with the other thalamic subdivisions exhibiting faint if any immunostaining.
These are not located in the Lateral Hypothalamus, were most orexin neurons are located, but targeted those regions (Supraoptic, Paraventricular Nucleus, and the Arcuate) should enhance the signaling of Vasopressin, Oxytocin, and Growth hormone-releasing hormone. Vasopressin and Oxytocin seem to have positive effects on Orexin signaling, and GNRH directly promotes Slow Wave Sleep so perhaps that’s why Sigma agonism seems to help in Hypothalamic neurogenesis. If someone knew of another reason why Sigma signaling seems to help, I’d highly appreciate the input.August 10, 2017 at 11:55 am #2852Pereise1Participant
Looks like Centella Asiatica (Gotu Kola) is another good option:
Enhancement of hippocampal CA3 neuronal dendritic arborization by Centella asiatica (Linn) fresh leaf extract treatment in adult rats.
Centella asiatica (CeA) is a creeper, growing in moist places in India and other Asian countries. Leaves of CeA are used for memory enhancement in the Ayurvedic system of medicine, an alternate system of medicine in India. In the present study, we investigated the role of CeA fresh leaf extract treatment on the dendritic morphology of hippocampal CA3 neurons, one of the regions concerned with learning and memory, in adult rats.
In the present study, adult rats (2.5 months old) were fed with 2, 4 and 6 mL/kg body weight of fresh leaf extract of CeA for 2, 4 and 6 weeks, respectively. After the treatment period, the rats were killed, brains were removed and hippocampal neurons were impregnated with silver nitrate (Golgi staining). Hippocampal CA3 neurons were traced using camera lucida, and dendritic branching points (a measure of dendritic arborization) and intersections (a measure of dendritic length) were quantified. These data were compared with those of age-matched control rats.
The results showed a significant increase in the dendritic length (intersections) and dendritic branching points along the length of both apical and basal dendrites in rats treated with 6 mL/kg body weight/day of CeA for 6 weeks. However, the rats treated with 2 and 4 mL/kg body weight/day for 2 and 4 weeks did not show any significant change in hippocampal CA3 neuronal dendritic arborization.
We conclude that constituents present in Centella asiatica fresh leaf extract has neuronal dendritic growth-stimulating properties.
Of course, the only way to get any benefit from any supplements is to make sure you get a quality, standardized extract. That means no grocery store brands, NOW or Nature’s Way products with questionable extraction methods and 0% bioactives. It has to be an extract standardized to Triterpene Saponins to get any benefit. That said, it seems to be the perfect comedown supplement for PWN in general:
1. Stimulates glutamic acid decarboxylase, which cleans up all that extracellular glutamate from Amps or (ar)modafinil (https://www.ncbi.nlm.nih.gov/pubmed/18066140)
2. Strongly anxiolytic, good for those on here that suffer from anxiety. Examinedotcom, which is normally very conservative in it’s opinions, says the following on their summary of Gotu Kola: “Animal studies suggest anxiolytic properties somewhat comparable to diazepam albeit requiring a higher dosage, and these may occur following a single dose of the supplement. They may occur even if the subject is not inherently stressed, albeit to a lesser degree than anxious/stressed subjects”. They also mention the following: ”
A 70% ethanolic extract of the aerial parts of centella asiatica at 500mg twice daily (1,000mg total) in persons with generalized anxiety disorder over the course of 60 days noted time dependent reductions in anxiety that reached 13.1% at 30 days and 26% at the end of the trial.
Comparable reductions were noted in self-reported stress (12.5% at 30 days and 23.2% at trial end) and depression (10.2% and 21.8%, respectively).”
Not a massive improvement but 26% is higher than the improvement in EDS I get from 20mg of dextroamphetamine so hey, why not?
3. While slightly lowering reaction time, it appears to raise cognition strangely enough. I took a dose of 1g last night (standardized to 5% saponins) and while I felt like I could still sleep if I wanted to, it was probably one of the most productive evenings I’ve had and I felt far better than I normally do when the stims wear off. Again, Examine had the following summary from a review of several studies: “The centella asiatica extract does appear to have inhernet cognitive enhancing properties, and while isolated asiaticoside is implicated in cognitive enhancement it seems that the water extract (lacking saponins) is also effective; suggesting that there are multiple bioactive components”.
4. Mild Gaba B agonist, which is the same function by which phenibut and GHB enhance slow wave sleep (http://www.sciencedirect.com/science/article/pii/S0944711311005034). Strangely, it doesn’t seem to cause dependence or withdrawal from any of the many reports I’ve read online.August 10, 2017 at 11:57 am #2853Pereise1Participant
Posted May 17 • Report post
On 5/17/2017 at 5:02 AM, Jasonm said:
It’s unknown if orexin neurons could be regenerated as far as I know. Neurogenesis was considered quackery not too long ago so there’s far more unknown than known. I’d almost guarantee you’d have to stop the damage before you’d see any benefit. The immune system is remarkably good at killing things. Neurogenesis is a slow process.
Some cases of narcolepsy may not be autoimmune at all and may have a slower clinical course. Most neurodegenerative diseases like PD are thought to result from oxidative stress. There seems to be some evidence of mitochondrial dysfunction in a subset of people with N, which might result in oxidative stress. There’s likely there’s not a one size fits all solution.
The simplest and probably most effective neurogenesis stimulator is exercise known to date.
@sometimes To piggyback on what @Jasonm mentioned, it’s well known that exercise potently stimulates neurogenesis: http://www.medicaldaily.com/pulse/adults-can-grow-new-brain-cells-how-neurogenesis-works-362826
As for whether or not it’s possible to regenerate orexin neurons, it’s been done in Rat models. Now, there isn’t a perfect rat model for Narcolepsy as no one has been able to find/describe an antibody to orexin yet, but it has been shown that with gene therapy, it’s 100% plausible that orexin neurons can be restored: https://www.ncbi.nlm.nih.gov/pubmed/23904672 (“Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice.”)
We can’t exactly replicate their methods just yet but it goes to show that the OX neurons should branch out again and return to normal function if neurogenesis is guided towards the lateral hypothalamus and once all rate-limiting obstacles are abolished. Even without eliminating the autoimmune attacks, it should be mathematically possible, considering there’s approximately 70,000 orexin neurons. They don’t usually die 100% even in NwC, and it’s known now that the brain can produce hundreds, even thousands of new neurons a day. It does this every day in the hippocampus (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394608/). Even in the hypothalamus, depending on the location, peptide neurons have been shown to penetrate a brain lesion and grow new peptidic neurons. This has been seen with Neuropeptide Y (https://www.ncbi.nlm.nih.gov/pubmed/8478986). So even if we’ve lost around 65,000/70,000 orexin neurons, even if we just regenerated 100 a day, it would theoretically only take 2 years to get back to 100%. I have no idea how many orexin neurons it’s possible to regenerate in a day, there hasn’t been nearly enough research, but it certainly seems possible if not probable given what we currently know is possible.
Just to add yet another reason to exercise, I found the following study on pubmed which tracked the prepro-orexin levels of high activity (HA) and low activity (LA) mice:
Prepro-orexin mRNA expression and rLH and SN orexin responsivity in HA and LA rats
As genetic manipulation of orexin expression levels directly alters SPAINT (24, 25) we hypothesized that differences in orexin contribute to differences in ambulatory SPAINT. Analysis of expression of the prepro-orexin mRNA (17) in cLH samples from HA (N = 18) and LA (N = 9) rats (Figure 1B) showed that HA rats had higher expression of prepro-orexin mRNA compared to LA rats (Figure 1C, Welch t-test, t = 2.73, df = 23.11, P = 0.012).
So I snooped around a bit for studies but I had a number of urgent surgery bookings today . That said, I found an interesting study, in Narcoleptic dogs, that showed that exercise only upped Orexin when the animals enjoyed it:
In a previous study we reported that Hcrt-1 levels in dogs were significantly increased by yard play (Wu et al., 2002), suggesting that the hypocretin system might be activated by motor activity. In the present study, however, we found that intense locomotor activity alone on a treadmill did not change CSF Hcrt-1 level compared to the control condition of simply standing on the treadmill, despite major changes in activity level, respiration, HR and body temperature. Clearly, changes in Hcrt release, as assessed by CSF level, are not required to mediate these phenomena. This contrasts with prior studies implicating Hcrt in mediating cardiovascular changes. However, these prior conclusions were all based on manipulations of the Hcrt system or examination of mutants rather than recordings of Hcrt release. Our results do not rule out the possibility of smaller changes that might not be detectable in the CSF. But they indicate that the magnitude of any such changes are significantly less than those produced by yard play. Furthermore our results show that great differences in locomotor speed, and the associated correlated changes in respiratory and cardiovascular activity during treadmill locomotion, produce no detectable change in CSF Hcrt level.
The emotional excitement that comes with social interaction with other dogs in the yard contrasts with the monotonous physical movement on the treadmill. Hypocretin neurons are heavily innervated by the amygdala and cholinergic arousal-related basal forebrain (Sakurai et al., 2005; Yoshida et al., 2006). They are activated by anticipation of positive reinforcements, such as food and opiate drugs (Boutrel et al., 2005; Harris et al., 2005; Mileykovskiy et al., 2005; Borgland et al., 2006), and during spontaneous wheel running (Anaclet et al., 2009; Furlong et al., 2009).
Heightened, and most often positive, emotions trigger cataplexy in Hcrt-deficient narcoleptic humans and animals (Guilleminault, 1976; Lin et al., 1999; Mitler et al., 1976). In humans, laughter is the most common trigger. During the yard play period, the dogs were free to engage in any activity, including digging holes in the grass, playing with toys and interacting with other dogs. When cages were opened for the daily exercise period, the dogs would run to the yard. In contrast, they generally had to be coaxed to go to the treadmill room. This behavior suggests that they enjoyed the free play more than the treadmill locomotion. However, once they were on the treadmill, they ran and elevated autonomic measures to levels comparable to those achieved during the yard play.
In conclusion, the present experiments show that motor activity and the associated autonomic and respiratory changes do not alter Hcrt level. We hypothesize that activity during positive emotions, of the sort that the dogs experienced during play behavior, is responsible for the increased Hcrt release we observed.
So basically any physical activity that we actually enjoy would be the best kind in our specific circumstances. However, I’m still not 100% sure because in non-narcoleptic humans, exercise did increase plasma orexin although that’s not always the best measurement: https://www.degruyter.com/view/j/jbcpp.2016.27.issue-6/jbcpp-2015-0133/jbcpp-2015-0133.xml?format=INTAugust 10, 2017 at 11:58 am #2854Pereise1Participant
Posted June 28 • Report post
Don’t know how I missed this one, but Forskolin looks like a high quality addition to any Pwn’s regimen:
Activity-dependent synaptic plasticity occurs in hypocretin/orexin neurons. We tested the ability of forskolin to induce LTP in hypocretin/orexin neurons to determine the mechanisms underlying the synaptic potentiation resulting from prolonged wakefulness. Bath application of forskolin, an activator of adenylyl cyclase, induces LTP at all synapses on neurons in the hippocampus (42–45). The forskolin-induced LTP (For-LTP) is PKA dependent, and the PKA cascade is right downstream to the activation of the D1 dopamine receptor (39, 43, 44). Bath application of forskolin for 10 minutes induced a long-lasting potentiation of spike firing in hypocretin/orexin neurons (Figure 5). This potentiation persisted for the duration of the experiment (more than 1 hour; n = 5; Figure 5A). For-LTP is dose dependent and can be observed at a concentration as low as 1 μM (Figure 5B). In slices pretreated with a membrane-permeable PKA inhibitor, KT5720 (20 μM), For-LTP of spike frequency was largely blocked (116.7% ± 15.4% of baseline; n = 7; P > 0.05; Figure 5C).
To sweeten the deal, it looks like Forskolin has some similarity to Vasopressin. Now, this might be conjecture, but as vasopressin activates orexin, this might just be the mechanism by which Forskolin induces long term potentiation in Orexin, or a separate, novel method of activating orexin. In either case, I went ahead and ordered some, and will be getting it Thursday or Friday. I’ll report back with results.August 10, 2017 at 2:00 pm #2864TheRabbitKingKeymaster
I read “foreskin” at first and was like “Do wut now?!”
My current jam: Anathema - SpringfieldAugust 11, 2017 at 4:05 pm #2955Pereise1Participant
I read “foreskin” at first and was like “Do wut now?!”
Lol when I find a study on the connection between foreskin and orexin, you’ll be the first to know =PNovember 11, 2017 at 1:07 pm #3896WWPParticipant
Go to sleep:
Easy on the mind altering drugs:
• If you take, or plan to take, mind-altering drugs or supplements, read this book first:
• Do not ever take internet health advice without first doing your own research, and always consult a health care professional. Each individual is unique - if you make a mistake, you may not be able to reverse the effects that may take decades to reveal themselves.
• Be kind to Mother Nature and the Little Ones! 🙂November 11, 2017 at 4:13 pm #3900JasonKeymaster
Great find, WWP!November 11, 2017 at 7:39 pm #3902FerretModerator
Absolutely fascinating! Thank you! I would also like to add this link that was shown on the page of your first link…
It is also important for “wake up”. When you read it WWP, would you please comment on its implications. Thanks.November 12, 2017 at 12:42 am #3907WWPParticipant
@Jasonm and @Ferret
Thanks! Lots of narco stuff all in one place. Ferret, I always feel better when I stick my head in a cold body of water, so maybe I snort a little blue-green algae and then the sun fixes me up optogenetically. 🙂
Here’s one for you, F.:
Here’s another ‘Stay Awake’:
From the above article:
Narco risk factor:
How many of you where born in March?
Bad ‘Cat’ Dog!:
So it all started in Sask–“atchewan” – Bless you! Who woulda thunk it?
Worst job for narcos:
lookout for lions
Sik3 and Nalcn:
Soon, maybe? 🙂
• If you take, or plan to take, mind-altering drugs or supplements, read this book first:
• Do not ever take internet health advice without first doing your own research, and always consult a health care professional. Each individual is unique - if you make a mistake, you may not be able to reverse the effects that may take decades to reveal themselves.
• Be kind to Mother Nature and the Little Ones! 🙂August 21, 2018 at 5:32 pm #7350Pereise1Participant
So I’ve found a few more things that are helpful for repairing the brain:
- Hyperbaric Oxygen Therapy:
Inflammation, angiogenesis, neurogenesis, and gliosis are involved in traumatic brain injury (TBI). Several studies provide evidence supporting the neuroprotective effect of hyperbaric oxygen (HBO2) therapy in TBI. The aim of this study was to ascertain whether inflammation, angiogenesis, neurogenesis, and gliosis during TBI are affected by HBO2 therapy.
Rats were randomly divided into three groups: TBI + NBA (normobaric air: 21% O2 at 1 absolute atmospheres), TBI + HBO2, and Sham operation + NBA. TBI + HBO2 rats received 100% O2 at 2.0 absolute atmospheres for 1 hr/d for three consecutive days. Behavioral tests and biochemical and histologic evaluations were done 4 days after TBI onset.
TBI + NBA rats displayed: (1) motor and cognitive dysfunction; (2) cerebral infarction and apoptosis; (3) activated inflammation (evidenced by increased brain myeloperoxidase activity and higher serum levels of tumor necrosis factor-α); (4) neuronal loss (evidenced by fewer NeuN-positive cells); and (5) gliosis (evidenced by more glial fibrillary protein-positive cells). In TBI + HBO2 rats, HBO2 therapy significantly reduced TBI-induced motor and cognitive dysfunction, cerebral infarction and apoptosis, activated inflammation, neuronal loss, and gliosis. In addition, HBO2 therapy stimulated angiogenesis (evidenced by more bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells), neurogenesis (evidenced by more bromodeoxyuridine-NeuN double-positive and glial cells-derived neurotrophic factor-positive cells), and overproduction of interleukin-10 (an anti-inflammatory cytokine).
Collectively, these results suggest that HBO2 therapy may improve outcomes of TBI in rats by inhibiting activated inflammation and gliosis while stimulating both angiogenesis and neurogenesis in the early stage.
To investigate whether hyperbaric oxygenation (HBO) can improve the recovery of motor functions in rats after suction ablation of the right sensorimotor cortex.
The experimental paradigm implies the following groups: Control animals ©, Control + HBO (CHBO), Sham controls (S), Sham control + HBO (SHBO), Lesion group (L), right sensorimotor cortex was removed by suction, Lesion + HBO (LHBO). Hyperbaric protocol: pressure applied 2.5 atmospheres absolute, for 60 minutes, once a day for 10 days. A beam walking test and grip strength meter were used to evaluate the recovery of motor functions. Expression profiles of growth-associated protein 43 (GAP43) and synaptophysin (SYP) were detected using immunohistochemistry.
The LHBO group achieved statistically superior scores in the beam walking test compared to the L group. Additionally, the recovery of muscle strength of the affected hindpaw was significantly enhanced after HBO treatment. Hyperbaric oxygenation induced over-expression of GAP43 and SYP in the neurons surrounding the lesion site.
Data presented suggest that hyperbaric oxygen therapy can intensify neuroplastic responses by promoting axonal sprouting and synapse remodelling, which contributes to the recovery of locomotor performances in rats. This provides the perspective for implementation of HBO in clinical strategies for treating traumatic brain injuries.
- Gastrodia Elata
Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism.
MATERIALS AND METHODS:
Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7.
GE treatment significantly improved the impaired locomotor functions induced by TBI.GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed.
GE treatment attenuated the locomotor deficit caused by TBI. The anti-inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain.
The mechanisms of agmatine-induced neuroprotective effects in traumatic brain injury (TBI) remain unclear. This study was to test whether inhibition of gliosis, angiogenesis, and neurogenesis attenuating TBI could be agmatine stimulated.
Anesthetized rats were randomly assigned to sham-operated group, TBI rats treated with saline (1 mL/kg, intraperitoneally), or TBI rats treated with agmatine (50 mg/kg, intraperitoneally). Saline or agmatine was injected 5 minutes after TBI and again once daily for the next 3 postoperative days.
Agmatine therapy in rats significantly attenuated TBI-induced motor function deficits (62° vs. 52° maximal angle) and cerebral infarction (88 mm vs. 216 mm), significantly reduced TBI-induced neuronal (9 NeuN-TUNEL double positive cells vs. 60 NeuN-TUNEL double positive cells) and glial (2 GFAP-TUNEL double positive cells vs. 20 GFAP-TUNEL double positive cells) apoptosis (increased TUNEL-positive and caspase-3-positive cells), neuronal loss (82 NeuN-positive cells vs. 60 NeuN-positive cells), gliosis (35 GFAP-positive cells vs. 72 GFAP-positive cells; 60 Iba1-positive cells vs. 90 Iba1-positive cells), and neurotoxicity (30 n-NOS-positive cells vs. 90 n-NOS-positive cells; 35 3-NT-positive cells vs. 90 3-NT-positive cells), and significantly promoted angiogenesis (3 BrdU/endothelial cells vs. 0.5 BrdU/endothelial cells; 50 vascular endothelial growth factor positive cells vs. 20 vascular endothelial growth factor-positive cells) and neurogenesis (27 BrdU/NeuN positive cells vs. 15 BrdU/NeuN positive cells).
Resultantly, agmatine therapy may attenuate TBI in rats via promoting angiogenesis, neurogenesis, and inhibition of gliosis.
We investigated the effect of taurine on inflammatory cytokine expression, on astrocyte activity and cerebral edema and functional outcomes, following traumatic brain injury (TBI) in rats. 72 rats were randomly divided into sham, TBI and Taurine groups. Rats subjected to moderate lateral fluid percussion injury were injected intravenously with taurine (200mg/kg) or saline immediately after injury or daily for 7days. Functional outcome was evaluated using Modified Neurological Severity Score (mNSS). Glial fibrillary acidic protein (GFAP) of the brain was measured using immunofluorescence. Concentration of 23 cytokines and chemokines in the injured cortex at 1 and 7days after TBI was assessed by Luminex xMAP technology. The results showed that taurine significantly improved functional recovery except 1day, reduced accumulation of GFAP and water content in the penumbral region at 7days after TBI. Compared with the TBI group, taurine significantly suppressed growth-related oncogene (GRO/KC) and interleukin (IL)-1β levels while elevating the levels of regulated on activation, normal T cell expressed and secreted (RANTES) at 1day. And taurine markedly decreased the level of 17 cytokine: eotaxin, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17, leptin, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and only increased the level of MIP-1α in a week. The results suggest that taurine effectively mitigates the severity of brain damage in TBI by attenuating the increase of astrocyte activity and edema as well as pro-inflammatory cytokines.
Vascular remodeling plays a key role in neural regeneration in the injured brain. Circulating endothelial progenitor cells (EPCs) are a mediator of the vascular remodeling process. Previous studies have found that progesterone treatment of traumatic brain injury (TBI) decreases cerebral edema and cellular apoptosis and inhibits inflammation, which in concert promote neuroprotective effects in young adult rats. However, whether progesterone treatment regulates circulating EPC level and fosters vascular remodeling after TBI have not been investigated. In this study, we hypothesize that progesterone treatment following TBI increases circulating EPC levels and promotes vascular remodeling in the injured brain in aged rats. Male Wistar 20-month-old rats were subjected to a moderate unilateral parietal cortical contusion injury and were treated with or without progesterone (n=54/group). Progesterone was administered intraperitoneally at a dose of 16mg/kg at 1 h post-TBI and was subsequently injected subcutaneously daily for 14 days. Neurological functional tests and immnunostaining were performed. Circulating EPCs were measured by flow cytometry. Progesterone treatment significantly improved neurological outcome after TBI measured by the modified neurological severity score, Morris Water Maze and the long term potentiation in the hippocampus as well as increased the circulating EPC levels compared to TBI controls (p<0.05). Progesterone treatment also significantly increased CD34 and CD31 positive cell number and vessel density in the injured brain compared to TBI controls (p<0.05). These data indicate that progesterone treatment of TBI improves multiple neurological functional outcomes, increases the circulating EPC level, and facilitates vascular remodeling in the injured brain after TBI in aged rats.August 21, 2018 at 5:42 pm #7352Pereise1Participant
Here’s a few more things that can help regenerate CNS scar tissue:
We previously reported that neuroinflammation contributes to the amnesia of AβPPswe/PSEN1dE9 Alzheimer’s disease model mice fed a high-fat diet to induce type-2 diabetes (T2DM-AD mice), but the underlying mechanism for the memory decline remained unclear. Recent studies have suggested that cholinergic modulation is involved in neuroinflammatory cellular reactions including neurogenesis and gliosis, and in memory improvement. In this study, we administered a broad-spectrum cholinesterase inhibitor, rivastigmine (2 mg/kg/day, s.c.), into T2DM-AD mice for 6 weeks, and evaluated their memory performance, neurogenesis, and neuroinflammatory reactions. By two hippocampal-dependent memory tests, the Morris water maze and contextual fear conditioning, rivastigmine improved the memory deterioration of the T2DM-AD mice (n = 8, p < 0.01). The number of newborn neurons in the hippocampal dentate gyrus was 1138±324 (Ave±SEM) in wild-type littermates, 2573±442 in T2DM-AD-Vehicle, and 2165±300 in T2DM-AD-Rivastigmine mice, indicating that neurogenesis was accelerated in the two T2DM-AD groups (n = 5, p < 0.05). The dendritic maturation of new neurons in T2DM-AD-Vehicle mice was severely abrogated, and rivastigmine treatment reversed this retarded maturation. In addition, the hippocampus of T2DM-AD-Vehicle mice showed increased proinflammatory cytokines IL-1β and TNF-α and gliosis, and rivastigmine treatment blocked these inflammatory reactions. Rivastigmine did not change the insulin abnormality or amyloid pathology in these mice. Thus, cholinergic modulation by rivastigmine treatment led to enhanced neurogenesis and the suppression of gliosis, which together ameliorated the memory decline in T2DM-AD model mice.
CBD was already reported to exert a marked anti-inflammatory effect through the A2A and 5HT1A receptors , , as well as to improve brain function . In addition, it has been already demonstrated that CBD markedly downregulate reactive gliosis by reducing pro-inflammatory molecules and cytokine release that strongly occurs in Aβ neurotoxicity. This activity was linked to its ability to act as a potent inhibitor of NFκB activation induced by Aβ challenge . The present findings, confirming the formerly obtained results and extending our knowledge about CBD pharmacology, indicate that a selective PPARγ activation occurs upstream to CBD-mediated NFκB inhibition. Such activation appears to be responsible for a large plethora of CBD effects. Indeed, the interaction of CBD at the PPARγ site results in a profound inhibition of reactive gliosis as showed by the reduction of both GFAP and S100B protein expression together with a marked decline of pro-inflammatory molecules and cytokine release observed in Aβ challenged astrocytes.
Ischemic stroke in rodents stimulates neurogenesis in the adult brain and the proliferation of newborn neurons that migrate into the penumbra zone. The present study investigated the effect of methylene blue (MB) on neurogenesis and functional recovery in a photothrombotic (PT) model of ischemic stroke in rats. PT stroke model was induced by photo-activation of Rose Bengal dye in cerebral blood flow by cold fibre light. Rats received intraperitoneal injection of either MB (0.5 mg/kg/day) from day 1 to day 5 after stroke or an equal volume of saline solution as a control. Cell proliferative marker 5-bromodeoxyuridine (BrdU) was injected twice daily (50 mg/kg) from day 2 to day 8 and animals were sacrificed on day 12 after PT induction. We report that MB significantly enhanced cell proliferation and neurogenesis, as evidenced by the increased co-localizations of BrdU/NeuN, BrdU/DCX, BrdU/MAP2 and BrdU/Ki67 in the peri-infarct zone compared with vehicle controls. MB thus effectively limited infarct volume and improved neurological deficits compared to PT control animals. The effects of MB were accompanied with an attenuated level of reactive gliosis and release of pro-inflammatory cytokines, as well as elevated levels of cytochrome c oxidase activity and ATP production in peri-infarct regions. Our study provides important information that MB has the ability to promote neurogenesis and enhance the newborn-neurons’ survival in ischemic brain repair by inhibiting microenvironmental inflammation and increasing mitochondrial function.
Ashwagandha (Withaferin A):
Results: WFA significantly improved neurobehavioural function and alleviated histological alteration of spinal cord tissues in traumatized mice. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) significantly increased in WFA-treated mice. Meanwhile, the expression of Nogo-A and RhoA remarkably decreased in the presence of WFA. Furthermore, the apoptotic cell death was attenuated in mice treated with WFA (31.48 ± 2.50% vs. 50.08 ± 2.08%) accompanied by decreased bax and increased bcl-2. In addition, WFA decreased the expression of pro-inflammatory mediators such as IL-1β (11.20 ± 1.96 ng/mL vs. 17.59 ± 1.42 ng/mL) and TNF-α (57.38 ± 3.57 pg/mL vs. 95.06 ± 9.13 pg/mL). The anti-inflammatory cytokines including TGF-β1 (14.32 ± 1.04 pg/mL vs. 9.37 ± 1.17 pg/mL) and IL-10 (116.80 ± 6.91 pg/mL vs. 72.33 ± 9.35 pg/mL) were elevated after WFA administration.August 22, 2018 at 7:21 am #7364JasonKeymaster
@pereise1 You may already be aware, but if not and for those that aren’t aware, I’d advise caution with methylene blue since it’s a MAO-A inhibitor. Obviously those can have some very serious side effects if taken with serotonin increasing medications so I’d say most people would probably be advised to avoid it.
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