Is­raeli Insight Into De­pres­sion Could Lead to New Fast-Act­ing Drugs

Changes in pre­vi­ously-over­looked brain cells called mi­croglia are seen to play a role in the de­vel­op­ment of de­pres­sion fol­low­ing chronic ex­po­sure to stress.

The Jewish Voice - - HEALTH - By: Abi­gail Klein Le­ich­man – Is­rael 21c

In ex­per­i­ments with an­i­mals, the Is­raeli re­searchers were able to demon­strate that com­pounds that al­ter the func­tion­ing of mi­croglia could serve as novel and ef­fi­cient an­tide­pres­sant drugs. “We were able to demon­strate that such mi­croglia-stim­u­lat­ing drugs served as ef­fec­tive and fast-act­ing an­tide­pres­sants, pro­duc­ing com­plete re­cov­ery of the de­pres­sive-like be­hav­ioral symp­toms, as well as in­creas­ing the neu­ro­ge­n­e­sis to nor­mal lev­els within a few days of treat­ment,” Yir­miya said.

Did you know that clin­i­cal de­pres­sion causes more years of dis­abil­ity than can­cer, HIV/ AIDS, and car­dio­vas­cu­lar and res­pi­ra­tory dis­eases com­bined? A ma­jor de­pres­sive episode oc­curs in five to seven per­cent of the world’s pop­u­la­tion ev­ery year, and one in six peo­ple will at some point suf­fer from the disease.

This is why sci­en­tists in Is­rael and else­where are con­stantly on the search for a bet­ter un­der­stand­ing of the bi­o­log­i­cal mech­a­nisms be­hind de­pres­sion, which the World Health Or­ga­ni­za­tion has deemed “the lead­ing cause of dis­abil­ity world­wide.”

A new study by He­brew Univer­sity of Jerusalem sci­en­tists, pub­lished in the pre­mier psy­chi­a­try sci­ence jour­nal Molec­u­lar Psy­chi­a­try in De­cem­ber, was un­usual be­cause it fo­cused on a type of brain cell pre­vi­ously over­looked by de­pres­sion re­searchers.

Prof. Raz Yir­miya, di­rec­tor of the He­brew Univer­sity’s Psy­choneu­roim­munol­ogy Lab­o­ra­tory, and his doctoral stu­dent Tirzah Kreisel, to­gether with col­leagues in Yir­miya’s lab and at the Univer­sity of Colorado, showed that changes in one type of non-neu­ronal brain cells – mi­croglia – play a role in the de­vel­op­ment of de­pres­sion fol­low­ing chronic ex­po­sure to stress.

Com­pris­ing roughly 10% of brain cells, mi­croglia rep­re­sent the im­mune sys­tem in the brain. How­ever, re­cent stud­ies have re­vealed that th­ese cells are also in­volved in phys­i­o­log­i­cal pro­cesses not di­rectly re­lated to in­fec­tion and in­jury, in­clud­ing the re­sponse to stress.

In ex­per­i­ments with an­i­mals, the Is­raeli re­searchers were able to demon­strate that com­pounds that al­ter the func­tion­ing of mi­croglia could serve as novel and ef­fici t an­tide­pres­sant drugs.

En­cour­aged by the find ings, the He­brew Univer­sity’s tech­nol­ogy trans­fer com­pany, Yis­sum, has ap­plied for a patent for the treat­ment of some forms of de­pres­sion by sev­eral specifi mi­croglia-stim­u­lat­ing drugs.

Of mice and mi­croglia

Most re­search into clin­i­cal de­pres­sion tar­gets the brain’s neu­ron cells, while the in­volve­ment of other types of brain cells has not been thor­oughly ex­am­ined, Yir­miya ex­plained.

Cu­ri­ous about the work­ings of mi­croglia, the re­searchers de­vised an ex­per­i­ment that mim­icked chronic un­pre­dictable stress in hu­mans — a lead­ing cause of de­pres­sion — by ex­pos­ing mice to re­peated, un­pre­dictable stress­ful con­di­tions over a pe­riod of five weeks.

The mice de­vel­oped be­hav­ioral and neu­ro­log­i­cal symp­toms mir­ror­ing those seen in de­pressed hu­mans, in­clud­ing a re­duc­tion in plea­sur­able ac­tiv­ity and in so­cial in­ter­ac­tion, as well as re­duced gen­er­a­tion of new brain cells (neu­ro­ge­n­e­sis). De­creased neu­ro­ge­n­e­sis is seen an im­por­tant bi­o­log­i­cal marker of de­pres­sion.

Dur­ing the fi st week of stress ex­po­sure, mi­croglia cells ac­tively pro­lif­er­ate and cause the pro­duc­tion of spe­cific infl mma­tory mol­e­cules, and then the cells be­gin to die. Over five weeks of stress ex­po­sure, this pat­tern re­sulted in a re­duc­tion in the num­ber of mi­croglia, and to a de­gen­er­ated ap­pear­ance of some mi­croglia cells, par­tic­u­larly in a specifi re­gion of the brain in­volved in stress re­sponse.

When the re­searchers blocked the ini­tial stress-in­duced ac­ti­va­tion of mi­croglia with drugs or ge­netic ma­nip­u­la­tion, they were able to stop the sub­se­quent mi­croglia cell death and de­cline, as well as the de­pres­sive symp­toms and sup­pressed neu­ro­ge­n­e­sis.

“We were able to demon­strate that such mi­croglia-stim­u­lat­ing drugs served as ef­fec­tive and fast-act­ing an­tide­pres­sants, pro­duc­ing com­plete re­cov­ery of the de­pres­sive-like be­hav­ioral symp­toms, as well as in­creas­ing the neu­ro­ge­n­e­sis to nor­mal lev­els within a few days of treat­ment,” Yir­miya said.

How­ever, th­ese treat­ments were not ef­fec­tive in mice that had al­ready been ex­posed to the five- week stress pe­riod and there­fore had a lower num­ber of mi­croglia at the start of treat­ment.

Based on th­ese findi gs, the investigators treated the “de­pressed” mice with drugs that stim­u­lated the mi­croglia and in­creased their num­ber to a nor­mal level.

“In ad­di­tion to the clin­i­cal im­por­tance of th­ese re­sults, our findi gs pro­vide the fi st di­rect ev­i­dence that in ad­di­tion to neu­rons, dis­tur­bances in the func­tion­ing of brain mi­croglia cells have a role in caus­ing psy­chopathol­ogy in gen­eral, and de­pres­sion in par­tic­u­lar,” said Yir­miya. “This sug­gests new av­enues for drug re­search, in which mi­croglia stim­u­la­tors could serve as fast-act­ing an­tide­pres­sants in some forms of de­pres­sive and stress-re­lated con­di­tions.”

Changes in brain cells in­volved in im­mune re­sponse may also trig­ger ma­jor de­pres­sion. Im­age via Shutterstock.com

Prof. Raz Yir­miya: “This sug­gests new av­enues for drug re­search.” Photo cour­tesy of the He­brew Univer­sity

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