Dystonias

Trimetazidine: increases guanine, adenosine-derivatives, decreasing i,x. 16387483

Purine TO Dystonia and Dyskinesia

Unifying dystonias:

Animal models used interchangeably between catatonia, LND, and PD

Lesch-Nyhan syndrome crossover: substantia nigra lesions 23975452, oxidopamine modeling 33450287.

Neurological and immune effects of Lesch-Nyhan syndrome were apparent early on: PMID 53661, confirming neuronal and immune cell sensitivity to purine-based changes.

Gout: no correlation 34946237 correlation 30611222, 18975349: mostly unclear

Awakenings: transition from dystonia to dyskinesia via L-DOPA, similar to course of PD, despite infectious source.

Amantadine: catatonia and PD treatment

Statin-induced myositis and catatonia: same clinical course, same biomarker, different treatment.

Adenosine-derivative depletion:

ATP/ADP:

Transcriptomics study shows down-regulation of A-derivative interconversion enzymes and up-regulation of adenosine deaminase 25597950

LND decrease in ATP 8750613

AMP: 

Parkinson’s psychosis includes hypersexuality

PD is associated with new (incident) epilepsy 29369409 and especially with status epilepticus 24315021

increased cortisol 30374595 is PD

Hypercoagulability is also seen in Cushing’s syndrome 23134530

Among the most common indirect risks of catatonia is hypercoagulability: PMID 29521882. This hypercoagulability is biochemical, not simply positional: PMID 19447502. Similar changes are noted in Parkinson’s disease PMID 34439949, although risk of DVT/PE is likely countered by Parkinsonism treatment. Treatments for hypercoagulability target adenosine-transport

Stroke circadian rhythm

Stroke, HTN (lack of Ao?) risk factors of PD 34946237

Adenosine:

PD progresses to bipolar-type psychosis 28106066 and can be treated with CBZ 19309760

Lack of typical sleepiness in catatonia patients treated with lorazepam (closely related to diazepam, with excellent evidence of ado deaminase and AMP deaminase activity), even at high doses.

cAMP: cAMP deficit: psoriasis on risk of Parkinson’s 27057013 (2016) 

Psoriasis and PD progression 35870136 (2022)

SAM-e: Treatment of PD increases SAM-e levels 16340382

SAM-e helps depression in PD 11104210

SAM-e helps dystonia in LND 24055166

Other purines:

u: Purine depletion as measured by low uric acid strongly correlated with worse PD outcomes 35208569

x: 

caffeine

Dysolipidemia is protective 34946237

Go/g: Recent conclusion is that adenosine and dopamine are opposite forces: if guanine/guanosine, rather than dopamine, then the relationship between the two is immediately clear: homeostatic interconversion of purines.

Following the apparent shared pathophysiology, an effective treatment for Parkinson's,

L-DOPA, was tested in Lesch-Nyhan syndrome, but was ineffective: PMID 21506156. 

The opposite hypothesis was also investigated by treating cellular models of Parkinson's disease with guanosine, which was effective: PMID 23241934.

Traditionally considered a mysterious cause of death of dopaminergic neurons in the substantia nigra: Purine targets are used in chemotherapy: guanosine/ guanine deficiency may cause SN cell death?

guanine/guanosine cross reactivity at D2/3 receptor

guanine/guanosine mediates dyskinesia in LID 32426479

g: Late-stage PNP up-regulation (25597950)

suggest guanine deficiency as underlying pathology

guanine-similar PD treatments including 

Quinpirole amelioration of MPP+ 23452092 (2013)

pergolide 

repurposed metformin 35008822

PNP inhibitors: prospective protection, adverse treatment

Allopurinol: protective in toxin PD PQ/MB 24680743, population (not sig) 34654239, case report 34062024

Captopril: protective in toxin MPP+ PD 24184050, population 24910980, case report 19205069, 3891084 (1985)

Amlodipine: protective in population Taiwan 24910980, different from diltiazem/verapamil Denmark population 20437557, case-report of amlodipine-induced PD 12210888

case reports of verapamil-induced PD 1290396, 7573102, diagnosed and treated as PD for years, L-DOPA-resistant 8504444.

Statins: hyperlipidemia is protective 34946237: patients with lower chol have worse symptoms only if chronic txt with statin 36209467, summary table 34064670 worsening treatment case-control 27304858, statins improve distortion in dopamine recptors in PD rats 16996211, membrane cholesterol and atorvastatin shows differences in response to meth vs. cocaine 36567004

Furosemide: population protective 36054665

PNP activators: beneficial for dystonia treatment, but exacerbating toxin PD

L-DOPA 9510422: exacerbates MPP+ toxicity 14565778

https://pubmed.ncbi.nlm.nih.gov/36303019/

cAMP methods paper

https://pubmed.ncbi.nlm.nih.gov/36352228/

Adenosine locomotion

PMID 30336179

Other lab

Thank you for your research! I was particularly interested to see your work regarding dopamine and adenosine and cAMP in locomotion.

I study Lesch-Nyhan and Parkinson's as models for treatment of acute dystonia and catatonia in psychiatric patients. As I have been reviewing the literature, especially comparing Parkinson's to Lesch-Nyhan disease, I am struck by the way that shared features, e.g. substantia nigra lesions PMID 23975452, adenosine deficit PMID 8750613, clinical dystonia, etc. are reproduced in a single-enzyme disease like Lesch-Nyhan disease. I believe that this may be due to significant cross-reactivity between dopamine and guanine: the push-pull relationship between adenosine and dopamine may be compensatory changes resulting from conversion of adenosine into guanine, consistent with gene expression changes in Parkinson's progression (decreased expression of adenosine-derivative interconversion enzymes, increased expression of adenosine deaminase, and increased expression of purine nucleoside phosphorylase PMID 25597950). Treating Parkinson’s cells with guanosine results in apparent improvement PMID 23241934. Adding to this evidence, when Parkinson's is treated, there is a compensatory increase in SAM-e (reversal of homeostatic need to convert adenosine to guanine) PMID 16340382. This is opposite of the observed effect: "[L-DOPA], which facilitates dopamine synthesis, led to a prominent decrease in SAMe concentrations in the brains of rats [9037574], and in whole blood [9217094] and cerebrospinal fluid (CSF) [2391519] in humans." 32466248

BTW, there is a clinical correlate to decreased cAMP: psoriasis is treated with a PDE4 (cAMP selective) inhibitor apremilast PMID 26481941 and worsened by adenylate cyclase inhibitor lithium PMID 6259263. Others have commented on the correlation between psoriasis and increased risk of Parkinson's PMID 27057013, recently reaffirmed to include worsening psoriasis correlating with worsening Parkinson's PMID 35870136. I have personally observed an unusually high frequency of psoriasis in patients with catatonia, resolving with treatment, although I've not yet written it up.

I'm looking for collaborators to write up some/ any of these possibilities, which I would expect to draw attention to your work. Are you available to discuss further? Do you have any recommendations for collaborators?

Dystonia is a sustained involuntary muscle contraction seen in disorders that vary by duration: life-long Lesch-Nyhan Syndrome, end-of-life Parkinson's disease, days to months of NMS or catatonia, or hours to days of antipsychotic side-effects (acute dystonia, Parkinsonian EPS).

Lesch-Nyhan Syndrome is caused by inadequate activity of HGPRT: PMID 14142409, a salvage enzyme for I,X,G derivatives. Without the benefit of salvage, excess uric acid production leads to severe psychiatric symptoms, dystonia, and gout: PMID 32310539.

Neurological and immune effects of Lesch-Nyhan syndrome were apparent early on: PMID 53661, confirming neuronal and immune cell sensitivity to purine-based changes.

Lesch-Nyhan syndrome demonstrates interdependence between I,X,G derivatives and “dopaminergic” neurons in the basal ganglia implicated in both Lesch-Nyhan Syndrome and Parkinson's disease: PMID 23975452.

Following the apparent shared pathophysiology, an effective treatment for Parkinson's, L-DOPA, was tested in Lesch-Nyhan syndrome, but was ineffective: PMID 21506156. 

The opposite hypothesis was also investigated by treating cellular models of Parkinson's disease with guanosine, which was effective: oxidopamine protection PMID 23241934, MPP+ protection 25174304 free. Guanine with modified ribose-portion (queuine) also protective 34379627, suggesting guanine is active site

Parkinson's disease may caused by G-derivative deficiency, rather than dopamine deficiency.

Guanosine: protective in a variety of neuropathologies 27002712, 

GNL1 binds GMP, Parkinson's genes 33305682

8-oxoguanine builds up in PD 17279544 free

4 weeks after unilateral infusion with 6-OHDA into the medial forebrain bundle, increased ADP hydrolysis +15%, AMP +25%, and GTP +41%, GDP hydrolysis -60%. extracellular purine hydrolysis is a key factor in understanding PD 21046237

Guanine-derivative receptors have yet to be identified 30459558

Several Parkinson's treatments more closely resemble guanine than monocyclic L-DOPA/dopamine. Treatment with guanine-similar compounds may be superior to treatment with L-DOPA. For example, rotigotine may alleviate the need for L-DOPA treatment: PMID 28548894. Apomorphine is used in L-DOPA-resistant cases: PMID 31869150. 

Pergolide is not commonly used anymore: but cabergoline is commonly used.

These clinical correlations are consistent with emerging evidence that Parkinson's may be caused by a G-derivative deficiency rather than dopamine deficiency.

Acute dystonia is most often recognized as a side-effect of antipsychotics. Metoclopramide is a rare example of a non-antipsychotic that can cause acute dystonia.

Metoclopramide shares structural similarities with 8-amino guanine, a purine nucleoside phosphorylase inhibitor: PMID 32910805. Metoclopramide worsens dystonia in Parkinson's disease: PMID 30642154, suggesting that dystonia may be caused specifically by guanine deficiency.

Oxidopamine and MPTP/MPP+ are toxins that cause Parkinsonism and are extensively used in Parkinson's research. Oxidopamine is a guanine analogue, with a slight modification to the location of the O. Supporting the single-etiology dystonia hypothesis, oxidopamine lesions are also used as a model for Lesch-Nyhan Syndrome: PMID 33450287. Lack of guanine measured in vitro HGPRT - cells 23859490.

Oxidopamine and MPP+ toxin models suggest guanine deficiency leading to cell death of (perhaps particularly guanine-deficiency sensitive) substantia nigra neurons, similar to the way that purine-analogue chemotherapy agents like cladribine are used to target leukemias.

MPP+ may approximate the ribose/nucleic base bond, the particular bond broken by PNP. Consistent with the proposed mechanism of action of captopril as hypoxanthine-similar product inhibitor of PNP, captopril protects against MPP+ toxicity: PMID 24184050.

Due to structural similarity, amlodipine, nifedipine, and other members of the dihydropyridine antihypertensive class would be expected to reversibly inhibit PNP. A population-level study suggests that dihydropyridines and ACE-inhibitors reduce risk of Parkinson's: PMID 24910980. It may be that these compounds decrease the effect of exogenous or endogenous MPTP-similar toxins.

L-DOPA has been shown to decrease guanosine and increase guanine: PMID 9510422, apparently increasing PNP activity.

Since apparent PNP inhibitors protect against parkinsonism-inducing MPP+, we would expect L-DOPA induced PNP activation to increase MPP+ toxicity, which is consistent with experimental results. MPP+ causes temporary (homeostatic?) increase in L-DOPA, which seems to contribute to MPP+ toxicity: PMID 14565778.

Many antipsychotics contain a structure similar to MPP+/ MPTP. Brief/ reversible PNP inhibition may be responsible for Parkinsonism and acute-dystonia as side-effects.

This effect is likely augmented in antipsychotics by the therapeutic anti-G-derivative effects.

Note that apine/epines are not listed here.

Several non-antipsychotics also contain a structure similar to MPP+/ MPTP. Brief/ reversible PNP inhibition may be responsible for Parkinsonism and acute-dystonia as side-effects.

Notice that sertraline, citalopram, escitalopram, and fluvoxamine are not listed here.

Amantadine has been one of the most persistent medications helpful in the treatment of Parkinson's: PMID 34678171, and seems to address the full range of Parkinson's symptoms.

Molecular binding simulations: PMID 35300368 note tight fit to a number of purine interconversion enzymes, especially those related to A-derivatives, suggesting that the adamantyl-group is sufficiently similar to bind with in place of a purine's 6-member ring.

Amantadine has also shown promise in treatment of catatonia: review PMID 35568040, systematic review: PMID 29398916, including this case of ECT-resistant catatonia: PMID 27527886, in pediatric catatonia: PMID 23258439 and in combination with olanzapine: PMID 18071103. Amantadine is considered the best-supported alternative treatment after -pam BZD and ECT: PMID 28917389.

Amantidine is also a second-line agent in the treatment of acute dystonia: PMID 10473482.

Cross-over benefits between treatment of Parkinson's, acute dystonia, and catatonia also lends support to a single-etiology dyskinesia hypothesis. 

Folic acid has a guanine-similar structure and has been shown in elevated doses, in LND cell culture, to reduce patterns associated with neurological problems PMID 32430324, perhaps by decreasing homeostatic conversion of adenosines into guanines.  IMG

Folate supplementation, perhaps even to a supratherapeutic level, is expected to have few adverse effects PMID 2667316, especially if Zn and/or B12 supplementation is also considered.

CoQ10 has been noted to improve statin-induced myositis, another dystonic reaction 17482884

Despite likely purine nucleoside phosphorylase inhibition (compare to 8-amino guanosine: PMID 23242185), pramipexole is used in Parkinson's. It may be that pramipexole provides adequate guanine replacement to counterbalance purine nucleoside phosphorylase inhibition. It may also be that the S-substitution changes the 8-amino group to something more like an 8-amide group?

Reports of NMS in the context of Parkinson’s medication withdrawal: PMID 1672810 confirm the single underlying pathology common to these two dystonic disorders.

Guanine deficit as a cause of dystonia provides an explanation for the common clinical paradox of simultaneous psychosis (typically considered a dopamine excess) and dystonia (typically considered a dopamine deficiency), frequently seen in Parkinson’s and catatonia. 

All G-derivatives share the phenylethylamine-similar structure closely associated with D2/D3 receptor stimulation and psychosis. Despite excess cGMP, GMP, or guanosine, inhibition of intermediate enzymes may cause a guanine deficit, presenting as dystonia with psychosis.

Among the few things known about the biochemistry of amyotrophic lateral sclerosis (ALS) is its association with flavin deficiency: PMID 23073612. One of the few medications used to treat ALS is riluzole: PMID 20236142. Riluzole has expected purine nucleoside phosphorylase inhibition (compare to 8-amino guanosine: PMID 23242185), allowing for increased salvage by inosine-guanosine kinase resulting in increased flavin production.

Decreased adenosine deaminase activity is associated with worse ALS outcomes 30698736, 34440231

Catatonia is classically described as dystonia with speech and motor latency typical of Parkinson's disease, but catatonia is reversible: recommended treatments include ECT and lorazepam or other -pam benzodiazepine: PMID 25538636. Clonazepam ODT can be helpful in patients with limited swallow. Amobarbital has also shown efficacy: PMID 1734740, but barbiturates are not safe for ongoing treatment. Severe catatonia and NMS (another clinical syndrome that presents with dystonia) are treated with dantrolene: PMID 3979279.

Each of these compounds has an apparent xanthine-identifying 2-oxo structure. Guanase product inhibition should allow replenishment of guanine.

Based on limited risk and chemical similarities to accepted treatments for catatonia, I have used buspirone as an adjunct in a case of non-psychotic catatonia, with apparent benefit. I have also prescribed naltrexone as an adjunct in a case of psychotic catatonia that required long-term lorazepam treatment, with apparent benefit. Consistent with a buspirone case report: PMID 22290846, and despite literature review suggesting safety of naltrexone in psychosis: PMID 28959434, psychosis seemed to worsen at higher naltrexone doses, consistent with repletion of G-derivatives via guanase product inhibition.

Both of these off-label treatments have significantly better safety profile than recommended high–dose lorazepam. Naltrexone raises the intriguing possibility of a long-acting injectable catatonia treatment in cases that might otherwise require chronic high-dose lorazepam treatment.

Ondansetron is serotonergic, but not typically considered psychoactive. Mitragynine is a psychoactive component of kratom. These two compounds are chemically similar, and both have an inosine-identifying 6-oxo group, although mitragynine’s is located on a phenyl ring, more similar to inosine, predicting better binding and stronger effect. Kratom’s effects are described as a combination of stimulant (increased G-derivatives?) and opiate (excess guanine from guanase inhibition), consistent with expected response to GMP reductase inhibition. Mild GMP reductase inhibition should be helpful for dystonia. I have seen a case of catatonia during kratom withdrawal.

Ondansetron has been noted to be helpful in treating dyskinsia in animal models of Parkinson's: PMID 30656239. A case report serendipitously mentions acute resolution of catatonia following administration of hydromorphone (guanase inhibitor) and ondansetron: PMID 32845105, unrecognized or explained by the author.

I have added TID scheduled ondansetron as an adjunct in a few cases of catatonia with poor nutrition: both nutrition and catatonia seemed to improve rapidly. 

Guanine deficit may be an underlying shared mechanism in all clinical manifestations of dystonia, providing a broader array of potential treatment options and therapeutic targets.

It is possible that chronic G-derivative deficiency leads to selective neuronal death described in chronic disorders including ALS, Lesch-Nyhan Syndrome, and Parkinson’s disease, and could be ameliorated by early treatment.

Statins adversely affect Parkinson's symptoms, in a way that may confirm mechanism of action. Statins are also associated with elevated CK and myositis which may be related to catatonia.

Lower motor dysfunction = dystonia worse with statins 34275907, 34347020

There have been new studies recommending ACE inhibitors to treat dyskinesias, including L-DOPA induced dyskinesias: PMID 28836869. This is consistent with the proposed mechanism for ACE inhibitors. Due to association with dystonias, statins may also be helpful. In the absence of dyskinesia, ACE inhibitors and statins may be expected to worsen dystonic symptoms: PMID 19205069, 27304858.

Curiously, some ACE inhibitors share chemical structures with L-DOPA and reserpine, and would therefore be expected to act both as PNP inhibitors and activators. Clinical trial of perindopril suggests that inhibition/dystonia is predominant: PMID 10800878. I am not aware of moexipril data.

Two experimental agents used in Parkinson's research as dopamine agonists, dinapsoline and dinoxyline incorporate flat phenyl rings, likely to increase flatness of these molecules. These also demonstrate that the phenylethylamine structure activates the dopamine receptor in the guanine conformation, rather than any other twist of the amine tail. IMG

Parkinson's is known to modify expression of several purine conversion enzymes, with changes in expression throughout the disease course: PMID 25597950. Decreased production of enzymes involved in A-salvage and interconversion predominate, and PNP is specifically highlighted.

Interestingly, these changes would be expected to drive increased G-derivative production, mirroring the pathologic changes anticipated in bipolar mania: in both cases, decreased A-derivatives are expected to result in a compensatory increase in G-derivatives due to purine interconversion/ salvage. As noted above, manic symptomatology often co-occurs with Parkinson's disease.

mentions a trial underway with oral inosine for PD: 28622913 IMG

reviewed here: 28124620 IMG

Epinephrine and norepinephrine can assume a shape that would be expected to induce PNP. Use of beta blockers in tremor is consistent: block epi/norepi --> decrease activation of PNP --> increase Go and reduce dyskinesia. The body does not increase or decrease epi/norepi in response to Parkinson's treatment: PMID 7895813.

Bupropion, which may block norepi/epi, has been associated with dystonia PMID 32854484, PMID 17534961, PMID 19910737 full IMG

Verapamil is an L-DOPA analogue that is widely available. Similar to L-DOPA, and forming a bridge between recognized VMAT inhibitors reserpine, and tetrabenazine, verapamil may induce Parkinson's PMID 8504444, apparently binding more tightly than L-DOPA (resistance to L-DOPA treatment above), but produce a more limited effect. (Other examples PMID 1290396 PMID 7573102) IMG

I have found CBZ/OXC to be clinically helpful in treating cases of dystonia. These compounds also share the proposed active site in L-DOPA. IMG

Consistent with proposed mechanism for bipolar being excess guanosine, verapamil may have value as an antimanic agent, although studies have been mixed: non-inferior to first line lithium PMID 1728160, inferior to lithium PMID 8968305, not splitting from placebo PMID 9659868. The presence of statins may be an unrecognized confounder, due to proposed PNP inhibition. Although amlodipine/nifedipine share calcium channel blockade, they are expected to inhibit PNP, rather than activate PNP like verapamil. Significant clinical difference in response have been noted PMID 11736880. Bipolar patients being treated with CCBs may benefit from replacing amlodipine/nifedipine to verapamil and temporary cessation of statins until acute symptoms are adequately managed. IMG 

Several supplements include naturally high levels of L-DOPA: sometimes in excess of pharmacologic recommendations. IMG

Trimetazidine is used as a performance-enhancing drug, or for tinnitus, where PNP activation would also be helpful. IMG

PD progresses to bipolar-type psychosis 28106066 and shows down-regulation of A-derivative interconversion enzymes and up-regulation of adenosine deaminase 25597950, consistent with proposed bipolar mechanism. PD treatment reverses this, increases A-derivatives 16340382. PD treatment reverses this, increasing SAM-e PMID 16340382. Normal physiology of locomotion was recently noted to entail both adenosine and dopamine pathways in opposition to one another PMID 36352228.

32905132 IMG

Drugs that are likely to prevent L-DOPA are PNP inhibitors: worsen existing PD.

Diuretics potentially preventative PMID 36054665, but HCTZ doesn't cross BBB

G-derivatives in smooth muscle:

GI: 20940015

uterus: 36542121

both guanine and dopamine measured deficiencies across multiple HGPRT negative neurons, despite increase in L-DOPA 23859490. SN dopaminergic neurons are particularly susceptible to purine changes: start with mouse dopaminergic neural cell line, create 10 mutants HGPRT negative, result in decreased dopamine synthesis/metabolism mRNA, 18313225

17448149.