Putting it all together: symptoms, treatments, and apparent purine imbalances on the same page!

Schizophrenia & Parkinson's

Clinical Spectrum of Dopamine Disorders

Parkinson’s disease and schizophrenia may be the heterogeneous clinical symptom-sets of opposite ends of the same dopamine-regulation spectrum. The cells affected are the same SNpc dopaminergic neurons in both disorders. In the lab, a pro-dopamine schizophrenia-inducing toxin protects against the anti-dopamine effects of a Parkinson’s-inducing toxin PMID 27647473. In the clinic, when low-dopamine Parkinson's disease is treated, excessive treatment results in high-dopamine (schizophrenia) symptoms. When high-dopamine schizophrenia is treated, excessively high doses result in low-dopamine (Parkinsonian) symptoms. Neuroleptic malignant syndrome was first identified as a severe side-effect of excess anti-dopamine schizophrenia treatment, but an analogue has been observed in a genetic low-dopamine disorder PMID 34765395, 38933625. Sometimes, pro-dopamine and anti-dopamine agents are given to the same patient: in an asymptomatic patient receiving both pro- and anti-dopamine treatments, withdrawing the pro-dopamine resulted in Parkinsonian dystonia PMID 16677982.

Dopamine Can Be Regulated by Purines

Dopamine regulation may be mediated by purines: lack of a single purine metabolism enzyme causes severely decreased dopamine and Parkinsonian dystonia in a genetic disorder called Lesch-Nyhan Disease (LND) PMID 19259384.

Parkinson's symptoms have long been correlated with uric acid levels (a purine). Sometimes, the specific circumstances of a Parkinson's diagnosis and treatment point to a purine connection. A patient newly diagnosed with Parkinson’s developed gout, a purine-based symptom, treated with allopurinol (a purine analogue that can be used to treat schizophrenia PMID 15694232), resulting in worsening Parkinson’s PMID 34062024.

Dopamine Production and Transport is Correlated with Guanine

Since LND is caused by a genetic change, it is possible to say that a single cell or cell culture has LND. When dopaminergic neurons (implicated schizophrenia and Parkinson's) with a variety of LND-causing mutations are studied, they have undetectable guanine levels PMID 23859490 and show dramatically decreased production of dopamine-creating and transporting enzymes PMID 18313225. These same enzymes are implicated in Parkinson’s disease.

In LND patients, mutations impairing gPRT activity (affecting guanine and guanine-derivative levels) are predictive of low-dopamine dystonic symptoms PMID 26067813.

In lab-based Parkinson's research, guanosine supplementation (guanine's precursor) is protective against PD-inducing toxins PMID 23241934, 30417317, 25174304 and mitochondrial metabolic changes PMID 25174304 and ameliorates dystonic PD symptoms in animal models PMID 18816792, 29046640.

Potential Mechanism: Unraveling G-quadruplexes

The mRNA of dopamine-creating and transporting enzymes often have a G-quadruplex structure, PMID 33305682, in which the strand folds on itself via guanine-based attraction PMID 32923997, 33483368, 32313204. Guanine in the surrounding matrix may interrupt this pattern (if present in sufficient quantity), allowing the quadruplex to unravel and the mRNA to proceed to protein production. Note that excess guanine in the matrix could potentially result in excess pro-dopamine protein production (resulting in schizophrenia?) by this mechanism.

Pro-dopamine Treatments Often Include Guanine-similar Structures

Several pro-dopamine medications mimic the chemical structure of guanine. The size of the rings doesn't seem to be as important as the location of the guanine-identifying nitrogen in comparison to two mostly-flat rings.

Most of these compounds don't mimic dopamine very closely: dopamine has only one ring, with a flexible (rather than fixed) nitrogen tail.

Guanine-Dopamine Ancillary Correlates

When LND cells are flooded with guanine-similar folate, characteristic excess purine-production stops. If instead the cells are flooded with folate-similar (but adenine, rather than guanine-similar) methotrexate, the excess purine-production persists PMID 32430324.

In the lab, guanine-similar queuine is protective against PD-inducing toxin MPTP PMID 34379627. I recently observed a case of dramatic improvement in a patient with PD incidentally prescribed guanine-similar (and low-risk) valacyclovir/acyclovir.

Another guanine-analogue

Acute dystonia/ Parkinsonian side-effects are traditionally treated with antihistamines, which may temporarily dislodge guanine-similar histamine from receptors. Without addressing long-term histamine regulation, these have limited efficacy in subacute or chronic symptoms.

Anti-dopamine Treatments Often Mimic Guanine With Tricks

Several anti-dopamine molecules also mimic guanine, but have evasive maneuvers at the guanine-identifying location:

clozapine, olanzapine, quetiapine, loxapine, and blonanserin add a bulky ring to the guanine-identifying nitrogen

Anti-dopamine Tricks (cont'd)

chlorpromazine and zotepine retain the flexibility to move the guanine-identifying nitrogen out of the way, hide-and-seek style, while xanomeline, thioridazine, fluphenazine, and remoxipride combine hide-and-seek with a bulky ring

Antipsychotic Tricks (cont'd)

the primary risperidone metabolite, paliperidone, uses an adjacent oxygen to make a carbon look close-but-not-quite-like the expected nitrogen, combined with a bulky ring

Allopurinol Mechanism Details

Purine-based treatment of schizophrenia is demonstrated with allopurinol, a purine-mimic whose accepted mechanism of action is changing purine metabolism. Allopurinol shows efficacy in treating schizophrenia PMID 15694232. Allopurinol is converted by the body (via hPRT) into allopurinol riboside, which inhibits the sole enzyme producing guanine PMID 121041, reducing post-PNP products. This effect was absent in a patient without hPRT activity (which converts allopurinol into allopurinol riboside), while moderately more hPRT activity is correlated to moderately more effect PMID 5441549.

Allopurinol often has a remarkably low risk-profile compared to other medications with antipsychotic properties. With a low enough risk, preventative treatment of people at high risk for psychosis may be appropriate, in addition to active treatment paranoia. It may also be low-enough risk to use as first-aid in patients experiencing uncomfortable symptoms during hallucinogen intoxication.

Guanine-Similarity Predicts Pro-Dopamine Action Better Than Dopamine-Similarity

Notice that the antipsychotics above consistently have a guanine-similar, dopamine-dissimilar nitrogen or, as in zotepine, xanomeline, or thiothixine (not pictured here), a mimic.

Add a nitrogen-mimic in the corresponding position to amphetamine and the result is cathinone (street-named bath salts): the pro-dopamine effect is magnified.

It may be that guanine-similarity is more important than dopamine-similarity in predicting therapeutic effects of both antipsychotic and pro-psychotic drugs.

Summary so far...

Low dopamine in SNpc neurons is associated with low dopamine-production enzymes and low guanine (in LND cell cultures).
Adding high-dose guanine-similar folate seems to reverse pathological purine metabolism patterns in a low-dopamine disease state (in LND cell culture).
Clinical treatment of low-dopamine disease states include adding guanine-similar pro-dopamine agents: at excessive doses, these guanine-similar agents can produce schizophrenia-similar symptoms.
Clinical treatment of high-dopamine disease states includes adding guanine-trickster agents: used excessively, these may result in low-dopamine (Parkinsonian) symptoms.

Reconsidering PD Pathophysiology: Low Uric Acid

Like some forms of depression, Parkinson's disease severity is correlated with low uric acid levels PMID 19822770. Less severe uric acid deficit is associated with less severe symptoms and slower progression PMID 21538532. In the lab, increasing uric acid-producing enzyme XOR is associated with worse PD symptoms while XOR knockouts have better PD symptoms PMID 23248282. But...

In Parkinson's disease patients, increasing uric acid levels via inosine supplementation does not slow disease progression PMID 34519802, nor is co-morbid gout protective PMID 26330027. This is consistent with predictions that while PD may be treatable by changing concentration of uric acid precursors, changing uric acid itself is unlikely to be corrective PMID 29137045.

In LND, low dopamine is associated with dramatically increased uric acid, suggesting that dopamine is not dependent on uric acid itself, but may be dependent on a uric acid precursor (i.e. guanine).

Reconsidering PD Pathophysiology: Impaired Arborization

Low dopamine has been blamed on poor neuronal arborization in LND (PMID 10760551, 3925393) and Parkinson's (PMID 18462474), but...

Evidence in hgPRT KO mouse PMID 17374562 suggests that severe dopaminergic dysfunction can occur in the absence of impaired arborization or other morphological changes. Impaired arborization can be reproduced by blocking production of guanine-derivatives (via IMPDH inhibition) PMID 15670649.

Guanine deficit could cause low dopamine and impaired arborization, but impaired arborization is unlikely to be an independent cause of low dopamine.

Reconsidering PD Pathophysiology: Oxidative Stress

Low-dopamine has been blamed on excess oxidative stress in Parkinson's PMID 24252804, 40162062, 12666096, but...

In some instances, the oxidative stress that has been measured to support this conclusion is oxidized guanine in DNA PMID 23143307, 17279544. While oxidized guanine seems to be specifically tied to alpha-synuclein pathology PMID 3774073, decreased non-oxidized guanine replacements is a much more direct rationale for increased oxidized guanine than generalized oxidative stress.

Reconsidering PD Pathophysiology: Energy Failure

Parkinson's disease PMID 39911281, 28341600, 24038413 and LND PMID 34214487, 36226509 are associated with energy failure, described as inadequate ATP to maintain normal cellular function. It is a mystery how or why this would be connected to Parkinson's disease symptoms. But...

ATP and other adenosine-derivatives could be converted to oxopurines as part of a homeostatic attempt to increase guanine levels. In autopsy studies, PD progression is correlated with changes in purine metabolism that would decrease adenosine-derivatives including ATP and increase oxopurines including guanine PMID 25597950. In PD patients prior to treatment, levels of adenosine-derivative SAM are decreased (perhaps indicating shunting), followed by significant increases following treatment PMID 16340382 (indicating recovery). We have published about similar flux decreasing adenosine-derivatives and increasing oxopurines in bipolar mania PMID 37820933.

Reconsidering Clinical Correlates of PD

Constipation is one of the earliest signs of Parkinson's disease PMID 29350301, 36470230, 37579786. Linaclotide treats constipation by increasing cGMP production PMID 29985664: could it be that the constipation that presages Parkinson's disease is caused by decreased guanine-derivative cGMP in the context of decreased guanine?

Other clinical correlates of PD may be related to decreased adenosine-derivatives:

seizures PMID 29369409, 24315021 and disrupted circadian rhythm PMID 31234200, 38424131, 38942041, 30228640, 21876839 may be attributable to adenosine deficit
psoriasis PMID 27057013, 35870136, which can be treated with cAMP-specific PDE4 inhibitor apremilast PMID 26089047, may be attributable to cAMP deficit. I have personally observed an analogous correlation between acute catatonia and comorbid psoriasis, with simultaneous resolution during treatment.
thrombosis (DVT/PE) risk PMID 37699515, 39263553, 38290377, 40035126 may be attributable to ADP deficit. Thrombosis risk is shared with other dystonic disorders, including catatonia PMID 27156025, 25004188. Acute changes in purine substrate levels have been shown to cause clinically significant changes in coagulation PMID 35091759, which is generally accepted as mediated by ADP purinergic receptor PMID 26359511, 38597172

These correlations suggest that measures to increase guanine may lessen the need for homeostatic shunting of adenosine-derivatives to oxopurines, simultaneously resolving what had previously been viewed as comorbid conditions.

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