Schizophrenia, tyrosinase, ginseng, capers, and tyrosinase inhibitors (tea, mate, kojic acid, etc.)

The Texas church shooting two days ago has been weighing heavily on me, for I have a relative with schizophrenia. She refuses mental health treatment. She showed signs of early schizophrenia as early as her adolescence in that she had no close friends despite being able to engage in work, social events, and family events relatively well. Cold, distant, and detached describes her pretty well back then. (http://schizophrenia.com/earlysigns.htm) Then over the next two decades came hypersensitivity, ruminating thoughts, suicidal thoughts and hostility, hygiene neglect, lack of insight, nonsensical logic, delusions, affective flattening, and abusive behavior. It's a horrible thing to watch happen to a loved one, especially because the person, due to brain dysfunction, is convinced that nothing is wrong with her and that her problems are all due to mistreatment by others.

I think that tyrosinase activity is a key to schizophrenia. Tyrosinase is a copper-containing enzyme that is connected to both melanin and dopamine production. Tyrosinase is expressed in the brain. (http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2005.03019.x/full) One way researchers bring about schizophrenia in lab rats is by giving them the copper chelator cuprizone. (https://www.pubfacts.com/detail/28989170/Olig2-Silence-Ameliorates-Cuprizone-Induced-Schizophrenia-Like-Symptoms-in-Mice, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058516/)  A look at an epidemiology map of schizophrenia quickly gives rise to a supposition that melanin and schizophrenia might be inversely related (https://en.wikipedia.org/wiki/Epidemiology_of_schizophrenia), and higher melanin appears associated with altered dopamine signalling-connected sensitivity (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569050/). Dopamine dysfunction is  involved in schizophrenia. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032934/) As rats grow up, their cutaneous tyrosinase goes from making dopamine to making melanin in a way that temporally mirrors the common adolescent/young adult onset of early signs of schizophrenia in humans. (https://www.ncbi.nlm.nih.gov/pubmed/12832289)

I did some searching to see what could upregulate tyrosinase expression or increase its activity. Lymphoid enhancer-binding factor-1 (LEF-1) regulates tyrosinase gene transcription; overexpression of LEF-1 increases tyrosinase gene promoter activity, while LEF-1 knockdown decreases tyrosinase expression. (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143142) This is a promising finding, for LEF-1 is underexpressed in schizophrenia patients. (http://europepmc.org/articles/PMC1888575) Components of ginseng root can upregulate tyrosinase expression, too (https://www.hindawi.com/journals/ecam/2014/892073/), and ginseng root extract does not have a net effect of suppressing tyrosinase activity (https://www.ncbi.nlm.nih.gov/pubmed/12808298).

There are a handful of studies to indicate that ginseng root might actually be able to help ameliorate schizophrenia. A small study nearly a decade ago found that schizophrenia patients who took panax ginseng (AKA Korean ginseng) were less likely to have "flat affect" and other negative symptoms (negative in the sense of there being an absence of normal motivation, pleasure, etc.); the dosage was 200 mg/day, and it was taken for eight weeks. (https://www.cbsnews.com/news/ginseng-may-help-treat-schizophrenia/) A 2015 study subjected pregnant mice to stress and then found that ginseng could reverse the prenatal stress-caused behavioral changes in the offspring. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249748/)

If ginseng can really help with schizophrenia, wouldn't it have been noticed sooner? Ginseng is very important in traditional Chinese medicine. However, something else is very important in Chinese culture: tea, which just so happens to inhibit tyrosinase. (https://www.medscape.com/medline/abstract/10576599) Moreover, throughout eastern Asia, people regularly eat foods containing kojic acid, an important tyrosinase inhibitor in the field of skin-lightening research. (https://www.ncbi.nlm.nih.gov/pubmed/27725765, https://www.researchgate.net/publication/289283346_Inhibition_of_tyrosinase_activity_on_dopamine_hydrochloride_by_kojic_acid)

There are many tyrosinase inhibitors that are in the human diet. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705500/) There's mate in South America. (http://www.koreascience.or.kr/article/ArticleFullRecord.jsp?cn=HJPHBN_2015_v41n4_391) Perhaps mate is why Uruguay has more of a schizophrenia burden than Argentina despite being full of European-ancestry people and otherwise having a similar diet, for Uruguayans are mate-obsessed. There's rosmarinic acid, named after the culinary herb rosemary, which contains it. (http://agris.fao.org/agris-search/search.do?request_locale=es&recordID=KR2005011915) There's arbutin, found in bearberries, pear skins, and wheat. (https://www.ncbi.nlm.nih.gov/pubmed/8632348) It would take a supercomputer (good thing we live in the 21st century) to calculate the tyrosinase inhibition caused by an individual's diet, and the frequency of intake of the inhibitors would also need to be taken into account, for rare is the person who eats rosemary all day, while green tea at every meal is the rule in Japan and mate lovers in Uruguay seem to spend every waking hour cuddling their mate gourds.

The human diet doesn't appear to contain much in the way of tyrosinase boosters (http://www.mdpi.com/1420-3049/22/8/1303/htm). There are capers (https://link.springer.com/content/pdf/10.1007%2F978-90-481-3419-9_127.pdf) and watery grapefruit and pomelo extracts (https://www.ncbi.nlm.nih.gov/pubmed/20857432).  And then there is the possibility of ginseng root candy being a tyrosinase booster, so I will probably be giving some to my relative for Christmas this year.* This paucity of dietary tyrosinase boosters compared with the plethora of tyrosinase inhibitors is exactly what one would expect to find with an intractable issue like schizophrenia, for if tyrosinase activity is a key to schizophrenia, any tyrosinase boosters in the diet should have started to make themselves manifest by now by decreasing the prevalence of schizophrenia where they are consumed. But who consumes pomelo extract and capers regularly? (Actually, the countries where capers are most often eaten do in fact mostly show up at the bottom of the list for schizophrenia burden...I'm starting to get cautiously optimistic about my little hypothesis....my relative is getting capers for Thanksgiving.) And any tyrosinase boost from ginseng root might have been noted earlier were it not for the simultaneous consumption of tyrosinase-inhibiting tea in China.

* As with everything, ginseng shouldn't be overused. There are published case reports of two men who ended up with manic psychosis from using huge doses of ginseng (15-20 grams/day). (https://www.researchgate.net/publication/261289619_Manic_Psychosis_Associated_With_Ginseng_A_Report_of_Two_Cases_and_Discussion_of_the_Literature) One can always get too much of a good thing.