Te kikorangi metilīni me ngā matū karere io: te serotonini, te dopamini, te GABA, me te asetilikōlini

E ai ki tētahi kōrero e rangona nuitia ana mō te kikorangi metilīni, ka whakapiki tēnei matū i te serotonini me te dopamini, ka whakatau i te GABA, ā, ka whakakoi i te asetilikōlini, i te wā kotahi. Ka whakakotahitia e taua kōrero ngā kitenga taiwhanga motuhake e whā hei pānga kotahi i roto i te tangata. I inea e ngā pepa rangahau i takea mai ai taua kōrero ngā whāinga rerekē, i ngā tauira whakamātautau rerekē, i ngā kukūtanga he tata ki te kotahi mano whakareanga te rerekētanga. Ina wehea ngā whāinga, ka puta he tirohanga whakamere ake, tūpato ake hoki i tā taua rerenga kōrero kotahi e whakaae ai.

He māmā te whakaaro matua. Ki te here tētahi rāpoi ki tētahi whākōkī i roto i te ipuipu whakamātautau, kotahi noa iho tana mahi: kua here ki tētahi whākōkī i roto i te ipuipu whakamātautau. Ko te whakarerekētanga rānei o te taumata o tētahi matū karere io i te roro ora ka whakawhirinaki ki te kukūtanga ka tae ki te kiko, ki te āhua matū o te rāpoi i tōna taenga atu, me ērā atu mahi katoa a te rāpoi i taua kukūtanga anō. I ia wāhanga i raro nei, ka tirohia tonu ēnei pātai e toru i te taha o te kitenga e hāngai ana ki a rātou.

Te serotonini: e rua ngā whāinga, e rua ngā kukūtanga

O ngā pūnaha e whā, ko te serotonini te mea e kaha rawa ana ngā taunakitanga. I ahu mai aua taunakitanga i ngā whāinga rāpoi motuhake e rua, ā, kaua ēnei e whakakotahitia.

Ko te whāinga tuatahi ko te monoamine oxidase momo A, te whākōkī kei ngā pungao e wāwāhi ana i te serotonini. Ka tautāwhitia te MAO-A tangata kua purea e te kikorangi metilīni mā te here kaha, me te Ki e tata ana ki te 27 nanomolar. Engari me tino teitei ake ngā kukūtanga kātahi anō ka pāngia te MAO-B, e whakaaturia ana i te rangahau nekeneke tauhohenga i hono ai te waikano ki te tāoke serotonini. I kitea taua aronga whiriwhiri anō e tētahi rangahau whai pānga i te kiko repe pineal o te kiore. I reira, nā te aukati MAO-A i piki ai ngā indole i ahu mai i te serotonini, i heke ai te hua pākia serotonini 5-HIAA, ā, i rerekē ai tētahi urupare whakatika tūnga o te poroka e hono ana ki te serotonini. I pūrongotia ēnei i te rangahau mō ngā waikano hāoratanga-whakaitinga me ngā indole pineal. E rua ngā tauira whakamātautau rerekē, kotahi tonu te aronga: he iti ake te wāwāhinga, he nui ake te serotonini e toe ana i ngā wāhi e tangohia ai e te whākōkī.

Ko te whāinga tuarua ko te pūkawe serotonini tonu. I ngā pūtau e whakaputa ana i te pūkawe tangata, ka whakaiti te kikorangi metilīni i te kapohanga o tētahi matū tīmatanga kōrekoreko me te serotonini kua tohua, me te IC50 e tata ana ki te 1.4 micromolar. I pēhi hoki i ngā ia hiko i whakaohohia e te serotonini i ngā hopukanga patch-clamp, e ai ki te rangahau tika i ngā āhuatanga o te kikorangi metilīni i te SERT. I tirohia e ngā kaituhi ngā whakamārama kē e kitea noatia ana, ā, i kitea kāore te pānga i whakawhirinaki ki te tuku tohu cGMP, ki ngā panonitanga konupūmā, ki te nui rānei o te pūkawe e puta ana i te mata pūtau.

Tirohia te āputa i waenga i ngā tau e rua. Kei te awhe nanomolar te tautāwhitanga MAO-A. Me tata ki te rima tekau whakareanga te nui ake o te waikano hei tautāwhi i te pūkawe. Tērā pea ka tino pā tētahi rahinga iti o te matū ki te whākōkī, engari ka paku noa iho te pānga ki te pūkawe. Ko te tangata e whakakotahi ana i ēnei hei kerēme kotahi mō te serotonini, e whakahanumi ana i ngā awhe horopeta rerekē e rua hei awhe kotahi.

Ko te whai take rānei o tētahi o ēnei whāinga ki te tangata e tango ana i ētahi atu rongoā e pā ana ki te serotonini he take rongoā, ā, kei te aratohu pāhekoheko rongoā tōna wāhi. Ka mahere tēnei tuhinga i ngā whāinga; kei taua whārangi ngā tohutohu haumanu.

Te dopamini: te taunakitanga hāngai ngoikore rawa

Mō te dopamini, me tino āta whakawhāiti ngā kōrero kia pono ai. Kāore he rangahau kua tino whakapūmautia e whakaatu ana ka aukati te kikorangi metilīni i te pūkawe dopamini, ka here tika rānei ki ngā pūwhiwhi dopamini. Ko te IC50 pūkawe o te 1.4 micromolar e whakahuahia nuitia ana nō te pūkawe serotonini, ehara nō te DAT, ā, kaua rawa e whakaingoatia anō hei hua mō te DAT.

Ko ngā taunakitanga kei reira he mea autaki kē. Nā te mea ka pākia hoki te dopamini e ngā whākōkī MAO, ka pupuri te tautāwhitanga MAO i te dopamini me te serotonini me te noradrenalini. I ngā tauira whakamātautau pungao, i aukati te kikorangi metilīni i te hurihanga o te tāoke io MPTP ki tōna tāoke e pā ana ki te pūnaha dopamini, he hurihanga nā te MAO-B. He rite te kaha ki tō te deprenyl, he rongoā mō te mate Parkinson, e whakaahuatia ana i te rangahau whakahohe koiora MPTP me ngā rangahau MAO-B e pā ana. Ka tāpiri ngā rangahau kararehe i ētahi kitenga wāhanga: he pikinga tata ki te toru whakareanga o te tukunga dopamini i te taumata taketake mai i ngā tapahanga kiko striatum o te kiore i te 10 micromolar. I rangahautia tēnei i roto i te horopaki tuku tohu nitric oxide, kaua hei aukati pūkawe. I muri i te hoatutanga horopeta ki te tinana whānui, he rerekē hoki ngā hua i ngā rohe rerekē, ā, i kitea e ētahi rangahau te pikinga o te serotonini me te noradrenalini, engari he paku noa iho te rerekētanga o te dopamini.

Nō reira, he taunakitanga tūturu mō te dopamini, engari he mea autaki. Ka ahu mā tētahi whākōkī e whakahaere ana i ngā monoamine maha i te wā kotahi, kaua mā tētahi whāinga motuhake mō te dopamini. Ki te kī tētahi ka whakapiki te kikorangi metilīni i te dopamini i roto i te tangata, kua hipa ia i te taahiraa e whakaaturia ai tērā i roto i te rangahau.

Te GABA: te aukati i te frein i te kōhao here

He tino tau te kitenga mō te GABA, ā, ka taupatupatu ki te ingoa kua hua mō te waikano. I ngā pūtau e whakaputa ana i ngā pūwhiwhi GABA-A tangata, ka tautāwhi te kikorangi metilīni i ngā ia hiko i whakaohohia e te GABA, ka tīmata i te takiwā o te 3 micromolar. Ko te IC50 e tata ana ki te 31 micromolar mō te huinga alpha1-beta2-gamma2 e kitea nuitia ana, i te rangahau hiko-whaiaroaro i mahere ai i te wāhi mahi.

Ko te mahere i te wāhi mahi te wāhanga whai hua. Ahakoa ngā irakētanga i te wāhi picrotoxin, i mau tonu te tautāwhitanga. Nā ngā whakataurite waeiti i whakakore ngā wāhi benzodiazepine me te konutea hei take. Engari, nā ngā irakētanga i ngā toenga waikawa amino e rua e mōhiotia ana ka hanga i te kōhao here GABA tonu, i tino whakaiti te aukati. E tohu ana tēnei he tauāraitanga whakataetae i te wāhi here matū whakaoho, kaua he whakarerekētanga allosteric i tētahi atu wāhi. I mau tonu te pānga puta noa i ngā huinga waeiti kei ngā hononga io me waho i ngā hononga io, ā, i tere ngaro i te horoinga atu o te matū.

Ka puta he taupatupatu tūturu me mārama te whakapuaki. Ko tētahi rāpoi e rangahautia ana hei tautoko i te pūmahara, ka pēhi hoki i te tuku tohu tautāwhi tere i roto i tētahi rīhi taiwhanga. Ko te puta rānei o taua pēhitanga i te roro ora ka whakawhirinaki ki te kukūtanga ā-rohe. He teitei te 31 micromolar ina whakatauritea ki te nuinga o ngā kukūtanga ka pā ki te tinana whānui, ā, ka kōrerotia tēnei i te wāhanga whakamutunga. Ko taua taupatupatu tonu te kitenga; hei whakatau, me whakahaere ngā whakamātautau kāore anō kia mahia e te tangata.

Te asetilikōlini: e rua ngā whāinga tauaro

E rua ngā kitenga mō te asetilikōlini e ahu tauaro ana, ā, koia tonu te take me pūrongo wehe.

I tētahi taha, ka tautāwhi te kikorangi metilīni i ngā whākōkī e tango ana i te asetilikōlini. I tautāwhitia whakataetaetia te acetylcholinesterase o ngā pūtau toto whero kau i te takiwā o te 0.57 micromolar, te whākōkī kau i te takiwā o te 0.42 micromolar, me te mahi esterase o te wē toto tangata i te takiwā o te 1.1 micromolar. I tautāwhitia hoki te butyrylcholinesterase i te awhe tata ki te 0.4 ki te 5.3 micromolar, e ai ki te momo kararehe me te tauira whakamātautau. Kua whakarāpopototia ēnei i te arotake o ngā mahi a te kikorangi metilīni i te pūnaha io. Mā te whakaroa i te tangohanga ka nui ake te matū karere e toe ana i te hononga io. Koinei anō te arorau kei muri i ētahi rongoā kua whakaaetia mō te mate Alzheimer.

Engari he here tō te tukanga matū. Mā te āhua kikorangi kua hāoratia e tautāwhi te whākōkī; kāore te āhua kore tae kua whakaitia e pēnei. I ngā whakamātautau roa e whai wā ai te waikano ki te huri ki tōna āhua kua whakaitia, ka pūrongotia he tautāwhitanga ngoikore ake nā taua take anake. Kei ia tau ine whakamātautau mō te cholinesterase tētahi taurangi kāore e kitea: e hia o te waikano i noho kikorangi tonu i te wā i inea ai.

I tērā taha, ka aukati te kikorangi metilīni i te pūwhiwhi nikotīni alpha7, tētahi o ngā pūwhiwhi e pāngia ana e te asetilikōlini. I tautāwhitia ngā pūwhiwhi alpha7 tangata i whakaputaina i ngā pūtau hua poroka, me te IC50 e tata ana ki te 3.4 micromolar, mā te tauāraitanga kore whakataetae, kāore e whakawhirinaki ki te ngaohiko, ā, kāore i whakarerekē i te kaha o te matū whakaoho. I te 3 micromolar, i whakakorea ngā urupare hononga io i whakaohohia e te kōlini i ngā tapahanga kiko hippocampus o te kiore, e ai ki te rangahau pūwhiwhi alpha7. Nō reira, i ngā kukūtanga iti micromolar e rite ana, ka pupuri te waikano i te matū karere, ka whakaiti hoki i te urupare o tētahi o ōna pūwhiwhi. Kāore e taea te whakatau i te pānga whānui ki te tuku tohu kōliniki mai i tētahi o aua kitenga anake. Ka hono taua rangirua ki ngā tuhinga rangahau whānui mō te mate Alzheimer, me te kōrero whai pānga mō ngā rangahau hinengaro me ngā rangahau mate, engari kāore e whakatauria i konei.

Te whakataurite, i te wāhi kotahi

E toru ngā whakareanga tekau te āputa i waenga i te whāinga tairongo rawa me te whāinga iti rawa te tairongo. Ko taua whānuitanga te kaupapa o tēnei tuhinga e whakaaturia ana i te ripanga kotahi.

Ka tae ēnei kukūtanga ki te roro?

Kāore he tikanga o tētahi tau nō te ipuipu whakamātautau mēnā kāore he tau kukūtanga i te tinana hei whakataurite. I muri i te werohanga horopeta kotahi tere ki te ia toto, e tata ana ki te 1.4 mg mō ia kg, kua pūrongotia ngā taumata toharite i te wē toto tangata e tata ana ki te 5 micromolar. Engari, i puta i tētahi horopeta 100 mg mā te waha ngā taumata i te toto katoa e tata ana ki te 0.08 micromolar i taua huinga tuhinga rangahau anō. I ngā rangahau tohatoha matū i te kiore, ka kitea ngā taumata i te roro e tata ana ki te tekau ki te rua tekau whakareanga o ngā taumata kei te toto e rere ana. Heoi, ko te waikano katoa kei te kiko kua whakahanumitia taua inenga, ehara ko te waikano herekore kua hāoratia kei tētahi hononga io. Mā te here ki ngā pūmua wē toto e tata ana ki te 94 ōrau, me te tohatoha ki ngā pūtau toto, ka heke anō te hautanga herekore.

Ina whakatauritea ki te ripanga, he āta rerekē ngā taumata o te tauira, kaua he kōwhiringa āe, kāo noa iho. Kei raro noa atu te kukūtanga tautāwhi MAO-A i ngā kukūtanga angamaheni ka puta i te hoatutanga ki te ia toto, ā, e hāngai ana taua tautāwhitanga ki ngā mātāpono rongoā ina hoatu pēneitia te waikano. Kei te awhe kukūtanga iti micromolar ngā pānga cholinesterase me te alpha7. Ka inaki ngā kukūtanga tihi nō te ia toto ki taua awhe, engari tērā pea kāore ngā horopeta noa mā te waha e tae atu. Ko te IC50 GABA-A o te 31 micromolar kei runga ake i te nuinga o ngā kukūtanga e tika ana kia puta i te tinana whānui. Nā reira, ko taua aukati te mea uaua rawa ki te whakapae ka puta i roto i te tangata katoa. Me whai ia haupae o tēnei whakataurite i taua kupu here anō: ko te kukūtanga whai take ko te waikano herekore, kua hāoratia, kei waho i ngā pūtau, kei te whāinga tonu. Kāore he tauira toto e ine tika ana i taua rahinga.

Ngā whakatau kaua e puta

Kāore tētahi haupae o te ripanga e whakapūmau ana ka whakapiki, ka whakaheke rānei te kikorangi metilīni i tētahi matū karere io i roto i te tangata i runga i te āhua ka taea te matapae. Ko te tautāwhitanga whākōkī i tētahi tauira kua purea, te aukati pūkawe i tētahi rārangi pūtau, me te tauāraitanga pūwhiwhi i tētahi tapahanga kiko, he taahiraa whakamātautau whakahaere tonu ia mea, he mea wehe i ngā āhuatanga tūturu o ngā hononga io. E whakaatu ana te wāhanga kōliniki i ngā kitenga pono e rua, engari nā ō rāua pānga tauaro ka rangirua te whakatau. Ko te whakamahinga tika o tēnei whārangi he mahere o ngā whāinga kua whakaaturia ka pāngia e te rāpoi, me te kaha o ia pānga kua tohua. Mā konei ka ū tonu te kōrerorero mō ngā tukanga ki ngā mea i inea tūturu. Mō te pāhekoheko o ēnei whāinga ki ngā rongoā kua tohua, ko te aratohu pāhekoheko te whārangi e kawe ana i taua kaupapa, me ētahi atu whakamārama i ngā tūāpapa mātai rongoā me te tuhinga hoa e whakamārama ana i ngā tukanga.