Neurotrophin 3 Regenerates Cochlear Synapses

https://www.nature.com/articles/srep24907

In acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and post-synaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery.



Recent work on noise-induced and age-related hearing loss shows that the most vulnerable elements in the inner ear are not the sensory cells, but their synapses with cochlear nerve terminals1. A noise exposure causing a large, but ultimately reversible, elevation of cochlear thresholds, can immediately, and permanently, destroy these synapses, thereby silencing up to 50% of the fibers in the cochlear nerve, despite no immediate or delayed loss of hair cells1,3. Although this cochlear synaptopathy does not elevate thresholds, the loss of neural channels likely causes difficulties understanding speech in noisy or reverberant environments2 and may also cause tinnitus3,4, the phantom sounds commonly brought on by acoustic overexposure. This type of cochlear synaptopathy has been called “hidden hearing loss”5, because the auditory deficits can hide behind a normal threshold audiogram.

In the adult ear, cochlear nerve fibers often degenerate after cochlear insult, including noise damage and ototoxic antibiotics6. This degeneration occurs with a variable time course, depending on the nature and severity of the insult; however, the unmyelinated terminal dendrites within the organ of Corti disappear first (within hours to days), followed more slowly by the peripheral axons in the osseous spiral lamina (within days to weeks), and, only on a much slower time course, the cell bodies in the spiral ganglion and their central axons that compose the cochlear nerve (over weeks to months and longer)7,8,9. Given that cochlear implants can continue to provide useful hearing for years after hair cell loss, these long-surviving neurons must remain electrically excitable and appropriately connected to their central targets10. Thus, in many types of sensorineural hearing loss, there is a long therapeutic window wherein a treatment to elicit neurite outgrowth could reconnect silenced cochlear ganglion cells with hair cells, and thereby potentially improve speech in noise performance and reduce tinnitus.

Neurotrophin-3 (NT-3) is a member of the neurotrophic factor family that contributes to neuronal differentiation, survival and axonal outgrowth via its interactions with TrkC receptors11,12. Neurotrophins are necessary for normal development of cochlear innervation13,14,15,16, and NT-3 is necessary for the formation and maintenance of hair cell ribbon synapses in the postnatal cochlea17. In the early postnatal ear, NT-3 is broadly expressed in the organ of Corti, but becomes restricted to the inner hair cells (IHCs) with a longitudinal gradient (apex > base) in the adult18,19.

Prior studies have shown that exogenous neurotrophins, delivered directly to the cochlear fluids, can prolong the survival of cochlear neurons after hair cell destruction by ototoxic drugs20. Furthermore, using transgenic overexpression of NT-3 by supporting cells in mice, we have shown partial synapse regeneration and partial recovery of cochlear neural responses after noise damage17. However, a more clinically relevant question is whether exogenous NT-3 can be locally delivered to the inner ear to reverse cochlear synapthopathy. Here, we show that NT-3, delivered at the round window, can regenerate hair cell synapses and restore sound-evoked neural function after a synaptopathic noise exposure. We also describe techniques for surgically accessing, and delivering drugs with a thermoreversible hydrogel to the round window in mice, without jeopardizing cochlear function. Considering that round-window drug delivery in humans could be accomplished via injection through the eardrum21, our results suggest a promising therapeutic approach for the treatment of cochlear synaptopathy, and for the tinnitus and auditory processing deficits it likely causes.

​

...

Read the rest in the full article:
https://www.nature.com/articles/srep24907

 

Herbal formula SYJN increases neurotrophin-3 and nerve growth factor expression in brain regions

https://www.ncbi.nlm.nih.gov/pubmed/20600769

AIM OF THE STUDY:
SYJN is a Chinese herbal formula that contains four herbs: Bupleurum chinense DC., Curcuma aromatica Salisb., Perilla frutescens (L.) Britt., and Acorus tatarinowii Schott. Previous studies conducted in our laboratory have revealed an antidepressant-like effect of the formula in chronic unpredictable stress (CUS)-induced depression model in rats. The present study aimed to investigate whether neurotrophin-3 (NT-3) and nerve growth factor (NGF) are involved in the antidepressant-like action of SYJN by using the same depressive model in rats.

MATERIALS AND METHODS:
Rats were subjected to an experimental setting of CUS. The mechanism underlying the antidepressant-like action of SYJN was examined by measuring protein and mRNA expression of NT-3 and NGF in brain tissues of CUS-exposed rats.

RESULTS:
The results showed that NT-3 protein and mRNA expression in the hippocampus and frontal cortex were significantly decreased in CUS-treated rats. CUS treatment also significantly decreased NGF protein and mRNA expression in the frontal cortex of the animals. Daily intragastric administration of SYJN (1300 or 2600 mg/kg/day) during the 4 weeks of CUS significantly suppressed these changes induced by CUS.

CONCLUSION:
The results suggest that the antidepressant-like activity of SYJN is likely mediated by the increases in NT-3 and NGF expression in brain tissues.


Matrine promotes NT3 expression in CNS cells

https://www.ncbi.nlm.nih.gov/pubmed/28392360

Abstract
Neurotrophin 3 (NT3) is a potent neurotrophic factor for promoting remyelination and recovery of neuronal function; upregulation of its expression in the central nervous system (CNS) is thus of major therapeutic importance for neurological deficits. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flavescent, has been recently reported to effectively ameliorate clinical signs in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by secreting antiinflammatory cytokines. In the present study, our goal was to investigate whether MAT could affect NT3 expression of glial cells in the CNS, the major cell populations in the CNS foci of MS/EAE. We found that MAT markedly upregulated NT3 expression in the CNS not only by microglia/macrophages and astrocytes, but also by oligodendrocyte precursor cells, indicative of both paracrine and autocrine effects on myelinating cells. While MAT treatment reduced the numbers of iNOS+ M1, but increased Arg1+ M2 microglia/macrophage phenotypes, NT3 expression was upregulated in both phenotypes. These results indicate that MAT therapy for EAE acts, at least in part, by stimulating local production of NT3 by glial cells in the CNS, which protects neural cells from CNS inflammation-induced tissue damage.

Matrine (MAT) effectively ameliorate clinical signs and demyelination of ongoing EAE.

MAT treatment enhances Neurotrophin 3 (NT3) expression in microglia, astrocytes and OPCs.

MAT induced NT3 expression in both M1/M2 microglia, especially in Arg1+ M2 cells.

We conclude that MAT therapy for EAE acts, at least in part, by stimulating glial cells to produce NT3.

 

https://www.activeherb.com/extract/kushen.shtml


Ku Shen
(Sophora Root, Radix Sophorae Flavescentis, 苦参)

https://pubchem.ncbi.nlm.nih.gov/compound/Matrine#section=Top
GHS Classification

Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 25 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H319 (96%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P264, P270, P280, P301+P312, P305+P351+P338, P330, P337+P313, and P501
(The corresponding statement to each P-code can be found here.)

However: https://pubchem.ncbi.nlm.nih.gov/compound/Matrine#section=Literature&fullscreen=true

I will definitely try it.

 

This is one of the few threads in alternative treatments that may not be actual BS. Regardless it needs serious investigation.

 

Curcumin

 

Curcumin is extracted from curcuma longa.

 

Not the same thing?

 

No. But the same family.
https://en.m.wikipedia.org/wiki/Curcuma_aromatica
https://en.m.wikipedia.org/wiki/Turmeric

 

https://en.m.wikipedia.org/wiki/Neurotrophin-3

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.

The protein encoded by this gene, NT-3, is aneurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a proteingrowth factor which has activity on certainneurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 was the third neurotrophic factor to be characterized, after nerve growth factor (NGF) and BDNF(Brain Derived Neurotrophic Factor).

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors.

 

Effects of BDNF and NT-3 on hair cell survival in guinea pig cochlea damaged by kanamycin treatment.
https://www.ncbi.nlm.nih.gov/pubmed/10424676

The aim of this study was to determine whether neurotrophic factors such as brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) would protect auditory hair cells from ototoxicity by aminoglycoside antibiotic. Twenty-seven Wistar guinea pigs were divided into three groups of nine animals each. BDNF and NT-3 (100 microg/ml) were delivered into the right scala tympani of guinea pig cochlea through a cannula-osmotic pump device. Artificial perilymph (AP) was used as control. Immediately after implantation of the device, each animal was given five successive doses of kanamycin (400 mg/kg). At 15, 30 and 60 days after infusion, surviving inner and outer hair cells were counted at each turn of every cochlea with a Philips 515 scanning electron microscope. Multiple comparison tests were carried out among the groups, using ANOVA and Dunnett T3/Tukey HSD. Protective effects of NT-3 on hair cells were observed at 30 and 60 days after kanamycin injection. BDNF had no protective effect on hair cells at 15 and 60 days, but some at 30 days. This study suggests that NT-3 and BDNF may protect against cochlear hair cell damage caused by kanamycin treatment. Possible mechanisms for the otoprotective effects were discussed. No single mechanism postulated can explain fully the results seen in this study. It is possible that the mechanisms act in concert to produce the observed effects, or there are as yet undiscovered mechanisms or secondary messengers responsible for the otoprotective

NT-3 and/or BDNF therapy prevents loss of auditory neurons following loss of hair cells.
https://www.ncbi.nlm.nih.gov/pubmed/8724667

Destruction of auditory hair cells results in a subsequent loss of auditory neurons. In situ hybridization and neuronal cell culture studies as well as analyses of the inner ears of neurotrophin and neurotrophin receptor gene knockout mice have shown that NT-3 and BDNF mediate both the development and survival of auditory neurons. In this study guinea pigs were exposed to the ototoxic combination of an aminoglycoside antibiotic and a loop diuretic and then received 8 weeks of intracochlear infusion of either NT-3, BDNF or NT-3 + BDNF to determine whether site-specific application of these neurotrophins could prevent the loss of auditory neurons that follows a loss of auditory hair cells. Infusion of either NT-3 or NT-3 + BDNF into the scala tympani resulted in a > 90% survival of auditory neurons while BDNF infusion yielded a 78% survival rate, compared with a 14-24% neuronal survival rate in untreated ototoxin-exposed cochleae. These results show that loss of auditory neurons that occurs subsequent to a loss of auditory hair cells can be prevented by in vivo neurotrophin therapy with either NT-3 or BDNF.

Expression of BDNF and NT-3 mRNA in hair cells of the organ of Corti: quantitative analysis in developing rats.
https://www.ncbi.nlm.nih.gov/pubmed/8157505

Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are synthesized by inner and outer hair cells of the developing organ of Corti. This raises the possibility that the reorganization of cochlear innervation patterns that occurs postnatally may be influenced by changing levels of neurotrophin expression. To determine if differential expression of BDNF or NT-3 in the inner and outer hair cells correlates with the reorganization of afferent and efferent innervation, we used in situ hybridization techniques to quantify relative levels of transcript biosynthesis in hair cells of developing rats. BDNF transcripts decreased in inner and outer hair cells from E17 to insignificant levels at P4. NT-3 expression was high at E17 in inner and outer hair cells, decreased in outer hair cells by E21, in inner hair cells by P1, remained low during the first postnatal week and was increased in the adult. The decreases in expression of both neurotrophins at birth precede the retraction of afferent nerve terminals from outer hair cells. BDNF and NT-3 transcription decreases substantially in outer hair cells between E21 and P4 when efferent innervation begins, indicating target biosynthesis of these neurotrophins is not likely to be instrumental in efferent target selection.

Influence of neurotrophins on the synaptogenesis of inner hair cells
https://www.ncbi.nlm.nih.gov/pubmed/12485622

The Bronx waltzer (bv) deaf mouse is characterized by massive degeneration of the primary auditory receptors, the inner hair cells, which occurs during the time of expected afferent synaptogenesis. The process is associated with degeneration and protracted division of the normally postmitotic afferent spiral ganglion neurons. To investigate the potential role of neurotrophins in the afferent synaptogenesis of inner hair cells, we exposed bv newborn cochleas in organotypic culture to brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF), and also to gamma aminobutyric acid (GABA), for up to 8 days. The study was done using light and electron microscopy. Only about 20% of the inner hair cells survived in culture, regardless of the treatment, similar to the number in the intact mutant in our colony. Depending on the exogenous treatment, this population consisted of either innervated ultrastructurally normal cells or denervated dedifferentiated cells wrapped-in lieu of nerve endings-by the supporting inner phalangeal and border cells. In the control and GABA cultures, inner hair cells were mostly denervated. BDNF and NT-3 alone or combined increased synaptogenesis and hair cell survival only during the first 3 days (by about 10%); however, the cells became denervated by 8 postnatal (PN). Only NGF induced stable innervation and differentiation of neurosensory relationships, including supernumerary innervation characteristic of the intact bv. Denervation among the remaining 20% of inner hair cells induced a reactive wrapping by inner phalangeal and border cells which evidently extended inner hair cell survival. Immunocytochemical studies of these reactive supporting cells were done in the intact (8 PN) mutant cochlea. The supporting cells that provide sustenance to the denervated inner hair cells displayed strong BDNF (and possibly NT-3) immunoreactivity. Subsequently, we revealed the presence of all three neurotrophins in the inner hair cell region of the developing (1-8 PN) cochlea of the normal ICR mouse. The inner hair cells expressed all three neurotrophins; BDNF prevailed in the inner phalangeal cells, NT-3 in the pillar cells and inner phalangeal cells, and NGF in the pillar cells.

IN CONCLUSION:
initially, the 80% loss of inner hair cells is apparently caused by their failed afferent synaptogenesis. Exogenous neurotrophins influence synaptogenesis in the bv in culture, but NGF alone is successful in promoting stable neurosensory relationships. The presence of neurotrophins in supporting cells in the normal and degenerating cochlea indicates their role in the sustenance of inner hair cells.

[NGF - this is contained in Lu rong - other thread in Alternative Treatment and Research]

 

It would be awesome if some natural substance could really heal us.

 

https://nootropicsexpert.com/13-nootropics-to-boost-bdnf/

Nootropics to Boost BDNF

• Ashwagandha
• Bacopa monnieri
• DHA (Omega-3)
• Ginseng
• Gotu Kola
• L-Theanine
• Magnesium
• N-Acetyl L-Cysteine (NAC)
• Noopept
• Rhodiola Rosea
• Pterostilbene
• Resveratrol
• Turmeric

 

Have you been able to try Sophora Root that you mentioned above? If so, was it useful to reduce your T? Thank you.

 

Neurotrophin-3 injections into the eardrum are safe. I can say that for an absolute fact.

 

Psychedelics (LSD, Psilocybin, DMT) boost BDNF and NGF as well. Lion's Mane boosts NGF too.

 

We probably already have a cure, the issue is it's sitting in a lab doing nothing.

 

I think for most of us the remedy will either come in the form of bimodal stimulation or hair cell regeneration. NT-3 doesn't seem to be too shabby either. Damn I have dropped so many clues.......

 

Why be so cryptic? Why not put it out there in black and white?

 

"BLUES CLUES" [That's The First...

It's going to be interesting to see the effects hair cell regeneration has on tinnitus once the trials are done. I'm still so new to all of this but it's made me pretty optimistic lately.

 

Here:
I can say for a fact that NT-3 and BDNF are safe when injected into a human's eardrum.
In a year or so when they report the phase 1 results for OTO-413, they will state that there were no adverse events. I'm not aware of anyone testing NT-3 in humans anytime soon, which is a shame.

 

How do you know that it's safe?

 

Does restoring synapses deplete any cells needed to restore them? Or are they different from hair cells?

 

Probably different.

 

I’m continuing my Noopept/L Theanine/Weed/LSD until Susan Shore’s device hits the market. My tinnitus is much lower these days, hopefully it’ll heal away. I don’t know if it’s from the stack I’ve been on or just natural healing but it is a ton better over this last year. Enough so that it doesn’t bother me from doing anything that I want to do in life. But still, I’d like it out of my head.

I’m probably gonna skip Lenire and wait for Michigan.

 

Out of curiosity, where did you get that information from?

 

Someone travels to another country at great expense to have a surgical procedure, in which he has said he can’t say too much because the procedure is pretty much proprietary...
And he says he knows some things and drops clues... cryptic yes... but obvious IMHO.

 

So...has it improved your condition to any extent?

 

So if we boosted NT-3 and BDNF through diet and supplements, then perhaps we can naturally restore our synapse nerve's? Is it even safe to try to "Boost" NT-3 and BDNF?

Drug: OTO-413
Single intratympanic injection of Brain-Derived Neurotrophic Factor (BDNF)

Look's like that's what Otonomy is using for OTO-413 phase 1. I must be missing something right?