Parkinson's Disease and Neurodegeneration: GABA-Collapse Hypothesis

[LAJ12345]

ncbi.nlm.nih.gov/pmc/articl...

This is quite old but interesting . GABA does seem to calm hubby when he is agitated.

“Neurodegenerative diseases constitute a heterogeneous group of age-related disorders that are characterized by a slow but irreversible deterioration of brain functions. Evidence accumulated over more than two decades has implicated calcium-related homeostatic mechanisms, giving rise to the Ca2+ hypothesis of brain aging and, ultimately, cell death. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the central (CNS), peripheral and enteric nervous systems. It appears to be involved in a wide variety of physiological functions within and outside the nervous system, that are maintained through a complex interaction between GABA and calcium-dependent neurotransmission and cellular metabolic functions. Within CNS the Ca2+/GABA mechanism stabilizes neuronal activity both at cellular and systemic levels. Decline in the Ca2+/GABA control initiates several cascading processes leading to both weakened protective barriers (in particular the blood-brain barrier) and accumulations of intracellular deposits of calcium and Lewy bodies. Linking such a vital mechanism of synaptic transmission with metabolism (both at cellular and tissue level) by means of a common reciprocal Ca2+/GABA inhibition results in a fragile balance, which is prone to destabilization and auto-destruction. The GABA decline etiology proposed here appears to apply to all human neurodegenerative processes initiated by abnormal intracellular calcium levels. Therefore, the original description of Parkinson's disease (PD) as due to the selective damage of dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder of the nervous system, whose clinical symptoms reflect the localization and progression of the most advanced GABA pathology. A future and more complete therapeutic approach to PD should be aimed first at slowing (or stopping) the progression of Ca2+/GABA functional decline.”

[LAJ12345]

Melatonin and GABA

pubmed.ncbi.nlm.nih.gov/226...

Abstract

In the present study, we investigated the effect of melatonin on the GABA-induced current (I(GABA) and GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in cultured rat hippocampal neurons using the whole-cell patch-clamp technique. We found that melatonin rapidly and reversibly enhanced I(GABA) in a dose-dependent manner, with an EC50 of 949 μM. Melatonin markedly enhanced the peak amplitude of a subsaturating I(GABA) but not that of a saturating I(GABA). Interestingly, melatonin was effective only when GABA and melatonin were applied together. Furthermore, the effect of melatonin on I(GABA) was voltage-independent and did not change the ion selectivity of the GABA(A) receptor. The melatonin enhancement on I(GABA) can not be blocked by luzindole, a melatonin receptor antagonist, indicating that melatonin-induced I(GABA) enhancement was not via activation of its own membrane receptors. However, this enhancement may be mediated via high-affinity benzodiazepine sites as it was inhibited by the classical benzodiazepine antagonist flumazenil, suggesting an allosteric modulation of melatonin by binding to the sites of GABA(A) receptors. In addition, melatonin increased both amplitude and frequency of GABAergic mIPSCs, indicating that melatonin enhances GABAergic inhibitory transmission. Hence, our observation that melatonin has an enhancing effect on the GABAergic system may implicate a potential pathway for the neuroprotective effects of melatonin.

[gwendolinej]

Does your hubby take melatonin?

Gwendoline

[LAJ12345 in reply to gwendolinej]

He has been taking 5 mg at night before bed.

Over the past 5 months he has had a worsening of symptoms meaning he is reacting to madopar every time he eats, with spasms then inability to move so it appears it has run out. So he has just had his madopar increased with an overnight slow release one added which has caused all kinds of problems with agitation and suicidal thoughts with serious intent and complete despair. So today I have reduced the number of day ones removing his first one of the day, dropping from 3 to 2 and spaced them out more, and have given him 3 mg melatonin at 11am to see if it can calm him. So far so good with the spasms, anxiety and shudders. Night is the worst thing so will see how it goes. The melatonin hasn’t made him sleepy in the day which was the worry.

[gwendolinej in reply to LAJ12345]

My husband has had his Madapar results checked quite a few times with the PKG device. He doesn’t have any visible side effects, in fact very little change at all. The device ( worn on the wrist) measures what happens when you take your Madapar and for how long it lasts. His shows on a graph that it spikes, but not like it should, and lasts for a very short time. He only takes 125 mg three times a day.

Does your husband take a GABA supplement?

I can’t remember, is your hubby using the Wellred coronet. We are using the coronet and their Therapad. My husband (Alan) had recently started jerking badly in bed. He’s always had restless legs. When we added the Therapad, the jerking stopped….probably about three weeks now. He’s taking 5mg of melatonin as well.

Alan’s been in hospital for a few days. His constipation problem has got so bad that our GP wants a thorough investigation. He’s on a liquid diet and is having a colonoscopy and gastroscope tomorrow.

I don’t know about you, but I’m exhausted.

Gwendoline

[LAJ12345 in reply to gwendolinej]

Yeah, me too. Couldn’t sleep last night as I was scared he was going to follow through with the jumping under a truck threat. And he can’t get back into bed so I worry about that with winter coming on. It will be too cold soon. I just went op shopping and bought some baggy woolen clothing he can wear to bed as pyjamas so he doesn’t need to get under blankets to keep warm. (His hands don’t work)And locksmith is coming soon to put nighttime deadlocks on our end of the house to confine him to bedroom hall and bathroom so hopefully he can’t get up to any harm. The other end of the house has a staircase and he has thrown himself down that once a long time ago . Now I can’t sleep listening for him being up roaming and wondering what he’s up to.

Yes, he takes gaba for anxiety which has worked well until the last few weeks. But lately he has had to have clonazapam 1/4 tablet of the low dose is enough to calm him, and if not he has another 1/4 half an hour later.

He has the red light which he enjoys but not the Thera pad. What is that?

What is a pkg device? Can you have one at home? I will google it. Madopar has been good for a couple of years. He started on sinemet but got changed to the Kinson version but could not tolerate that. Then madopar.

[kevowpd in reply to LAJ12345]

What does his neurologist say about all of this? Most notably the suicide threats?

[LAJ12345 in reply to kevowpd]

We are still waiting for last May’s appointment (2021) to come around. He has seen him twice in 4 years such is the queue. The same specialist is the private specialist and public one. But you have to pay $1200 to see him if you go private which we did last time, for 90 minutes where there is not really any advice given, just measurements taken, and the same sort of advice about diet and exercise you can get anywhere. . But the doctor has now fast tracked him an appointment with the hospital clinic. Really the services here are appalling.

[Hidden in reply to LAJ12345]

Oh I am so deeply sorry you and your husband are going through this. 6 years ago my Dad with PD kept talking about suicide. He was 77 at the time. I contacted Adult Protective Services, paid out of pocket for an in home neuro psych evaluation, went to multiple neurologists, etc etc. I feared for my safety as he came after me in a rage. The stress of this (and more that I won’t share at this time) took a toll on me obviously.

The next couple of years he developed petrifying dreams and was a danger to himself and others.

But now, at 83 with extremely advanced PD, he is calm. My Mom said he even seems happy. He was upbeat when she recently visited him. We are mystified. The doctor of course has no explanation.

I’m hoping that sharing this can bring a little hope.

It is hard for me to share these things. But sometimes we have to be vulnerable to seek support and give support.

When I had truly lost hope and was so desperate and beyond distraught, he turned a corner and is more peaceful now.

Your dear Hubby can pull through this. ❤️

[LAJ12345 in reply to Hidden]

Thank you. Trouble is he is just 62 and we have teenagers at home so it is traumatic for them too as they have to tip toe around trying not to make a noise and of course they don’t always feel like being considerate. It’s not fair on them. They can’t have friends over or make any noise in the common areas. It’s like he has become autistic in his ability to handle stimuli of any kind including noise, light, food, sights or activitities out of the normal.

[Hidden in reply to LAJ12345]

Interesting you mention behaviors similar to autism spectrum. I’m researching this bc I relate to it. This video starts out very annoying but it gets better. I was looking for the paper he is referencing. The kynurenin pathway is associated with neurological disorders like PD as well.

I think PD and autism have a lot in common.

youtu.be/vAgD1CdNUTQ(Not working as expected?)

[LAJ12345 in reply to Hidden]

He has always been very particular and obsessive especially when stressed. To the point he would get upset if the toddlers underpants weren’t folded into tiny little parcels and arranged neatly in their drawers. And pity help anyone who rummaged in those drawers and disturbed the little parcels! But unfortunately it never followed through to eg cleaning. I always found it a bit irrational but it must have been a control mechanism to feel he had some order.

[Hidden in reply to LAJ12345]

PD, OCD and autism are all inflammatory conditions. I know you know that but stating it to explain why I’m sending this link. webmd.com/mental-health/new...

[LAJ12345 in reply to Hidden]

Interesting, I suspected as much.

[Millbrook in reply to LAJ12345]

Hugs. Praying for you and yr husband.

[LAJ12345 in reply to Millbrook]

Thanks.

[gwendolinej in reply to LAJ12345]

You are going through a very difficult period. Hopefully it will all calm down soon, as it has in the past. We are so lucky to have this forum.

Alan attended the Movement Disorder Clinic at the Royal Melbourne Hospital, initially, which is where we found our neurologist, who we now see privately. The clinic worked well, as Alans symptoms weren’t and still aren’t, “the garden variety”…our neurologist’s words…. no tremor. The clinic is overseen by Andrew Evans, an amazing man, who mentored our neurologist.

Is the hospital clinic you are going to a Movement Disorder clinic? If so, like us, you may find a new neurologist. Both Andrew Evans and our neurologist and many others, work in the public system and privately. The reason our neurologist started his own practice was that he didn’t want to be dictated to as to how long he spent with a patient. He isn’t taking any new patients, as he is so busy. We certainly don’t pay anywhere near that amount and we can see him as often as we feel we need to. We made an appointment in late December for early May. We can cancel if we don’t need it. He also has staff we can talk to…the nurse or the Practice Manager, both are fabulous and so caring. We are so lucky. I tell you this because there has to be someone better than you have. You are very astute, so I’m sure there’s a way to find that person.

The PKG device comes from a company called Global Kinetics. It’s ordered by the neurologist. The company rings you, gets the times you take the Madapar, and sends you the watch, which has an alarm to remind you to take your tablet. After a week, you post the watch back to the company and they send a report to the neurologist.

Re the Therapad…google red light therapy pd research au. Click on the surfershealth site and see video interview with Professor Hosen Kiat. Our neurologist says that Professor Hosen Kiat has an excellent reputation.

Alan has been put on two antidepressants, Escitalopram and Mirtazapine. In early November he was admitted to hospital at the request of our neurologist after he completely closed down . He’d been confused for a few weeks and then he just refused to do anything…take his meds, leave our unit. When I asked him why, he’d say “there’s no point”. When I asked what he meant, he’d say “ I don’t know”.

In hospital he saw our neurologist and a psychiatrist (it’s called neuropsychiatry apparently, something new). After 4 weeks he was sent to rehab, where he spent another four weeks. Mentally, he’s been fantastic ever since. What he was diagnosed with was Delirium. We don’t know what caused it. We are concerned that the antidepressants are adding to his constipation problems and a couple of other problems.

Did you ever try mannitol?

Regards and a big hug,

Gwendoline

[LAJ12345 in reply to gwendolinej]

Thank you❤️

That is what happened when hubby took mirtazapine and why I weaned him off it over years. I feel it brought the PD on. Making him apathetic. In the end I had it dilated by a compounding pharmacist to 3.25 mg then diluted that to 1/10 eventually for months until he could be free of it. Nasty stuff. You might find he does better on a lower dose of it if he is like hubby.

[LAJ12345]

genengnews.com/news/cinnamo...

Cinnamon and GABA.

“In the current study, Dr. Pahan and his colleagues first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. Surprisingly, when the researcher’s analyzed the disparities between the good and poor learners, they found differences in two brain proteins—gamma-aminobutyric acid (GABA) A receptor, alpha 5 (GABRA5) and cAMP response element binding protein (CREB). When the poor-learning mice were fed cinnamon, the gap was all but erased.

[Hidden]

This is so informative. I will need to reread multiple times. Amazing it’s 20 years old.

[LAJ12345 in reply to Hidden]

Yes, I’m not sure if it has been superseded but gaba certainly helps calm hubby

[chartist]

LAJ,

I'm a little late to this thread, but what do you think caused this serious turnaround in your husbands condition because he was previously doing very well?

Art

[LAJ12345 in reply to chartist]

Not sure but I suspect the vaccine

[chartist in reply to LAJ12345]

If you have already written about his symptoms post vaccine, can you link me to it?

Art

[LAJ12345 in reply to chartist]

I’ve sort of explained above if you can look at my comments.

[chartist in reply to LAJ12345]

Okay, I responded below.

Art

[chartist in reply to LAJ12345]

LAJ,

Here is something you can check on your husband since the neurologist can not see him immediately. The vaccine is noted for causing swollen lymph nodes, especially on the side that the vaccine was given. The easiest ones to check are in his armpit. If they are swollen, this could be contributing to his increased symptoms. Even if they are swollen, he may not be aware of it.

health.clevelandclinic.org/...

This is a known issue with the vaccines and is not normally an issue in most people and when it occurs, it usually resolves on its own within 2 weeks. If it goes beyond two weeks you should let his doctor know immediately. Unfortunately, PwP have an issue with the lymphatic system in the area of the brain where the lymph system around the brain tends to move slowly and swollen lymph nodes could slow the lymph system in this area and this could exacerbate PD symptoms as the lymph system is not able to perform optimally to help rid fluids and waste products from the system.

scienceofparkinsons.com/202...

LAJ, I just wanted you to be aware of it and if there is no swelling you can cross it off the list of possible problems or if there is swelling you can take steps to help the lymph system get moving such as lymph massage or rebounding or at a minimum you can let his doctor know.

I hope things turn around for him soon because it is a hard way for all of you to live after him doing so well for such an extended period.

Art

[LAJ12345 in reply to chartist]

Thanks. Interestingly our teenage son has had swollen lymph nodes for months so I thought it was glandular fever.

I just checked and it doesn’t seem to be swollen but I’m not exactly sure what to look for.

[chartist in reply to LAJ12345]

Let us know what you find if you check your husband's lymph nodes.

Art

[chartist in reply to LAJ12345]

In the armpit, it will feel puffy and not as concave looking or feeling. You should be able to compare it to your son's if his lymph nodes are still swollen.

Art

[LAJ12345 in reply to chartist]

Yes, think his are ok. No swelling I can feel. My sons are around his neck

[chartist in reply to LAJ12345]

youtu.be/IOeeuIZSnig(Not working as expected?)

[LAJ12345 in reply to chartist]

That is interesting. When I do this on myself I feel like a draining of fluid down the top back of the roof of my mouth and my sinuses seem clearer. Weird.

I don’t know if you remember a year or so ago I had the weird feeling in the back of my head that felt like a lump and the feeling like fluid building up in my head when I lay down. Doctor kept saying it was anxiety. I went to ent dr, had mri, cat scan. Nothing showing. Then I went to Chinese traditional dr and got cupping and diaphragm release massage and have carried on stretching my neck , back, hips etc every day and it is nearly right. The lymph node exam did the same release of liquid.

[chartist in reply to LAJ12345]

the downside to the lymph node exam is that it can be rather uncomfortable all the way to painful if the nodes have swelling because you really have to dig in. Rebounding is not uncomfortable at all and can get the lymph fluid moving better and if you do it enough may help alleviate a little anxiety.

So did you retry on your husband and swollen lymph nodes are now ruled out?

Art

[LAJ12345 in reply to chartist]

He’s playing bridge on the pc and not interested in being poked and prodded at the moment. As the day draws on his tolerance level to anything decreases.

He gets night terrors now. Once it is nearly bedtime he almost has a panic attack at the thought of having to go to bed . It is is so odd. The locks are on the doors now with the key around my neck as he nightly now is trying to get out to throw himself under s truck. Vey stressful

[chartist in reply to LAJ12345]

Does increasing his melatonin dose lower his anxiety level?

Art

[LAJ12345 in reply to chartist]

I’ve only tried as much as 5 mg at night plus 3 mg in the afternoon but it didn’t seem to make a difference. Trouble is it is illegal to get here except with prescription, dr is unlikely to prescribe large amounts and it is hit and miss if companies will send it to me. I’ll order it once then next time they block it but seem to miss a slightly different brand or size or type of tablet for a while before they slap a ban on that. I don’t want to run out of everyday stuff as I only have a small stockpile.

[chartist in reply to LAJ12345]

Okay, do you know where his vitamin D level is? Low calcidiol can increase anxiety and you said you are approaching winter which means his calcidiol level is likely declining. Calcidiol /25 OH d level is very important in PD.

ncbi.nlm.nih.gov/pmc/articl...

Vitamin D insufficiency can also raise inflammatory levels :

healthunlocked.com/cure-par...

His poor sleep quality is increasing his inflammatory level :

sciencedaily.com/releases/2...

Art

[LAJ12345 in reply to chartist]

He takes 12 Hardys daily essential nutrients each day so that contains 96mcg 480% DR. He hasn’t been tested lately but the last few times on Hardys he has been at the top or slightly over the range. I think he should be ok.

The only other possible cause is I have been busy for the last couple of months working on a rental property so not around as much as usual so he has been sitting at his computer much of the time. He has been walking at least 90 minutes a day though still.

Since being on Hardys all the blood levels for everything has been very good especially for his age.

[chartist in reply to LAJ12345]

How tall is your husband and how much does he weigh? That is less than 4000 iu day, which is a fairly low dose. The 25 OH d range for vitamin D testing is 30 - 100 ng/ml. If he is sick and he is sick, you should try for the upper end of that range.

Vitamin D level has an inverse correlation with PD, so keeping levels higher in the range is useful :

ncbi.nlm.nih.gov/pmc/articl....

People with PD have lower levels of vitamin D than healthy controls :

ejnpn.springeropen.com/arti....

It can take 2 weeks for a supplement of vitamin D to be converted to the active form in the body.

Art

[LAJ12345 in reply to chartist]

He is 6 foot 2. Ok I will get it checked out if I can but he is very resistant to testing of any kind so might not be able to unless doctor forces him to have other tests and they agree to tag it on the end. Here they don’t test for it, just assume everyone is deficient in winter and prescribe a once a month over winter 50,000 pill. Last time he had one of those was before he was on the Hardys and it made him quite sick. I think like everything thing else he doesn’t process it efficiently.

We have just had summer though and he has been in the sun every day and he has been deteriorating over the summer so I don’t think it is that.

We now have an appointment for the neurologist on Monday finally. He was a bit better yesterday so stopping the tamsulosin has helped I think.

[JCRO in reply to LAJ12345]

Be VERY careful stopping tamulosin at short notice. It’s being taken to allow the patient to urinate, obviously. If you can’t pee it’ll be a trip to an ER/A&E. I’ve moved from tamulosin to Terazosin under the guidance of my urologist - as tamulosin might not be the best choice for a gentleman with PD - as I posted yesterday (another thread). Just stopping one therapy without substituting a replacement doesn’t strike me as the best idea. If your husband gets into trouble with his waterworks get the tamulosin into him fast. I’m not a doctor amd, accordingly, had to make the switch under proper supervision. It has to be a switch not a unilateral abandonment of a necessary medication.

[LAJ12345 in reply to JCRO]

He only took 2 days so doctor says it is ok. He wasn’t having trouble peeing as such, just had to go in the night a few times so doctor thought it might be enlarged prostate. Due to his agitated state an examination wasn’t possible

[JCRO in reply to LAJ12345]

👍