CIR­CA­DIAN RHYTHMS

THE IN­STA­BIL­ITY OF THE ADULT BRAIN

The McGill Daily - - Contents - Tony Feng The Mcgill Daily

In 1972, a group of re­searchers at Stan­ford Univer­sity dis­cov­ered that the en­zymes that reg­u­late choles­terol syn­the­sis in rats were most ac­tive at night. In 1999, choles­terol-low­er­ing drugs, such as Sim­vas­tatin, were found to be most ef­fec­tive when taken at bed­time. In the fol­low­ing years, sci­en­tists at­tempted to un­cover the rea­sons for th­ese ob­ser­va­tions. They found that the su­parchi­as­matic nu­cleus (SCN), a re­gion in the brain con­sist­ing of around 20, 000 neu­rons, is re­spon­si­ble for this phe­nom­e­non. The SCN acts as an in­ter­nal clock that keeps track of time and drives our cir­ca­dian rhythms– changes in hor­mone lev­els, be­hav­iour, and so on in a 24-hour cy­cle.

Many an­ti­bod­ies and hor­mones are pro­duced rhyth­mi­cally in our body. For ex­am­ple, mela­tonin is pro­duced at night to help peo­ple sleep. The con­cen­tra­tion of cor­ti­sol, a hor­mone pro­duced in re­sponse to stress, peaks in the morn­ing and de­creases as the day goes on. Th­ese rhyth­mi­cal changes can have many im­pli­ca­tions on clin­i­cal treat­ments. This April, Jy­oti Mad­hu­soodanan, a writer for The Sci­en­tist, spoke to var­i­ous re­searchers on this is­sue.

Re­searchers at the Univer­sity of Birm­ing­ham dis­cov­ered that among peo­ple who re­ceived the sea­sonal in­fluenza vac­ci­na­tion, those who re­ceived the treat­ment in the morn­ing had higher an­ti­flu an­ti­bod­ies than those who re­ceived it in the af­ter­noon. This sug­gests that the vary­ing lev­els of hor­mones and an­ti­bod­ies at dif­fer­ent times of the day al­tered the ef­fec­tive­ness of the vac­cine. The lead re­searcher of the study, Anna Phillips Whit­taker, noted that if the tim­ing fac­tor was con­sid­ered in clin­i­cal treat­ments, it would have a sig­nif­i­cant im­pact on health. “It’s such a sim­ple, low-risk in­ter­ven­tion that’s free to do, and could have mas­sive im­pli­ca­tions for health,” said Whit­taker.

Be­sides vac­ci­na­tions, epi­demi­o­log­i­cal data have shown that clin­i­cal treat­ments for ill­nesses such as arthri­tis, can­cer, and al­ler­gies can be more ef­fec­tive if they are ad­min­is­tered at cer­tain times of the day. This idea of timed treat­ments is known as chronother­apy; it has ex­isted for more than five decades, but has not been very pop­u­lar among physi­cians. In re­cent years, re­search in molec­u­lar bi­ol­ogy has fur­ther sup­ported this con­cept. In a 2014 study done in the Univer­sity of Penn­syl­va­nia, John Ho­ge­nesch and his col­leagues dis­cov­ered that 56 of the top 100 best-sell­ing drugs in the U.S., such as es­omepra­zole, arip­ipra­zole, and du­lox­e­tine, can cause pe­ri­odic ex­pres­sions in cer­tain genes in mice. Ho­ge­nesch was pos­i­tive about the fu­ture of chronother­apy be­cause “now we have the ground­work to pre­cisely un­der­stand a per­son’s clock and lever­age that in­for­ma­tion for bet­ter health.” He claimed, “be­cause of the molec­u­lar work, we’ve opened new doors here. This [idea] is not com­ing from left field any­more.”

Nev­er­the­less, in­te­grat­ing chronother­apy into clin­i­cal treat­ments has a long way to go. Sci­en­tists who work on chronother­apy still face skep­ti­cism from the sci­en­tific com­mu­nity. In ad­di­tion, putting chronother­apy into prac­tice poses a lot of chal­lenges be­cause each per­son’s cir­ca­dian rhythms are dif­fer­ent. Also, ob­tain­ing ap­proval from the FDA to im­ple­ment time- of-the- day in­di­ca­tions for drugs has many ob­sta­cles. “Many of th­ese ob­ser­va­tions are in the sci­en­tific lit­er­a­ture but not on drug la­bels,” said Ho­ge­nesch. His team is cur­rently try­ing to change this sit­u­a­tion by in­ves­ti­gat­ing ex­actly how the time of the day im­pacts the ef­fec­tive­ness of treat­ments, and by how much.

Re­flect­ing back on the past re­search on chronother­apy, Stan­ford psy­chi­a­trist David Spiegel noted, “We’ve learned enough now to know that there are rel­a­tively easy-to- do, low-risk things that may have an ef­fect on disease out­comes… I’d be sur­prised if there were any disease that didn’t have some cir­ca­dian com­po­nent.” To many chrono­bi­ol­o­gists, time is of­ten ne­glected when doc­tors con­sider the right treat­ment and the right dosage for pa­tients, and physi­cians should pay more at­ten­tion to this im­por­tant fac­tor be­cause “time of­fers an­other way to be pre­cise,” said Ho­ge­nesch.

Laura Bren­nan | The Mcgill Daily

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