Neurotoksin

Neurotoksin je termin izveden iz starogrčkih reči: νευρών (nevron) „žila“ i τοξικόν (toksikon) „toksin“. Neurotoksini su velika klasa eksogenih hemijskih neuroloških štetnih materija^[3] koje mogu negativno da utiču na funkciju tkiva u razviću, kao i zrelog nervnog tkiva.^[4] Ovaj termin takođe može da se koristi u klasifikaciji endogenih jedinjenja koja u abnormalnim koncentracijama mogu da budu neurološki toksična.^[3] Mada su neurotoksini često neurološki destruktivni, njihova sposobnost da specifično deluju na nervme komponente je važna u izučavanju nervnog sistema.^[5] Uobičajeni primeri neurotoksina su olovo,^[6] etanol,^[7] glutamat,^[8] azot-monoksid (NO),^[9] botulinski toksin,^[10] tetanus toksin,^[11] i tetrodotoksin.^[5]

Neurotoksinsko dejstvo se može okarakterisati inhibicijom neuronske kontrole jonskih koncentracija duž ćelijske membrane,^[5] ili komunikacije između neurona preko sinapse.^[12] Lokalna patologija izlaganja neurotoksinu često obuhvata neuronsku ekscitotoksičnost ili apoptozu,^[13] kao i oštećenje glijalne ćelije.^[14] Makroskopske manifestacije izloženosti neurotoksinima mogu da budu znatna oštećenja centralnog nervnog sistema poput mentalne retardacije,^[4] persistentnog oštećenja memorije,^[15] epilepsije, i demencije.^[16] Osim toga, neurotoksinom posredovano oštećenje perifernog nervnog sistema kao što je neuropatija ili miopatija je često. Postoje brojni tretmani čiji je cilj ublažavanje neurotoksinima posredovanih povreda, npr. primena antioksidanasa,^[7] antitoksina^[17] i etanola.^[18]

Zaleđina

Izloženost neurotoksinima nije nova pojava. Civilizacije su bile izložene neurološki destruktivnim jedinjenjima hiljadama godina. Jedan značajan primjer je moguće znatno izlaganje olovu u Rimskom carstvu usled razvoja obimnih vodovodnih mreža, i prakse kovanja vina u olovnim posudama da bi postalo slađe, procesom kojim se formira olovo acetat, poznat kao "olovni šećer".^[19] Neurotoksini su nezamarljiv činilac ljudske istorije, zbog krhke i osetljive prirode nervnog sistema, što ga čini veoma sklonim poremećajima.

Nervna tkiva prisutna u mozgu, kičmenoj moždini, i periferiji sačinjavaju izuzetno složen biološki sistem koji u velikoj meri definiše mnoštvo jedinstvenih svojstava osobe. Kao i kod svakog drugog visoko kompleksnog sistema, međutim, čak i male perturbacije njegovog okruženja mogu da uzrokuju znatne funkcionalne poremećaje. Neke od karakteristika koje čine nervni sistem visoko podložnim su velika površina neurona, njihov visok lipidni sadržaj u kome se zadržavaju lipofilni toksini, visok krvni protok u mozgu koji indukuje povišeno efektivno izlaganje toksinu, i postojanost neurona tokom životnog veka osobe, što dovodi do nagomilavanja oštećenja.^[20] Konsekventno, nervni sistemi poseduju brojne mehanizme koji ih štite od unutrašnjih, i spoljašnjih napada, uključujući kvrno moždanju barijeru.

Krvno-moždana barijera (BBB) je kritičan primer zaštite koji sprečava toksine i druga neželjena jedinjenja da dospeju do mozga.^[21] Pošto su mozgu potreban unos hranljivih materija i uklanjanje otpada, on je protkan krvnim sudovima. Krv može da nosi brojne toksine, koji imaju sposnost uzrokovanja neuronskih oštećenja. Stoga, zaštitne ćelije zvane astrociti okružuju kapilare mozga, apsorbuju nutrijente iz krvi, i naknadno ih transportuju do neurona, čime efektivno sprečavaju pristup mozgu za potencijalno štetne hemijske materijale.^[21]

Ova barijera stvara čvrst hidrofobni sloj oko kapilara u mozgu, koji inhibira transport velikih hidrofilnih jedinjenja. Pored BBB, vasoganglion pruža zaštini sloj protiv apsorpcije toksina u mozgu. Vasoganglioni su vaskularizovani slojevi tkiva prisutni u trećem, četvrtom, i lateralnim moždanim komorama, koji su putem funkcije njihovih ependimskih ćelija odgovrni za sintezu cerebrospinalnog fluida (CSF).^[22] Selektivnim propuštanjem jona i nutrijenata i blokiranjem pristupa teškim metalima kao što je olovo, vasoganglioni održavaju strogo regulisano okruženje kojim je obuhvaćen mozak i kičmena moždina.^[21]^[22]

Pojedina jedinjenja, među kojima je deo neutoksina, mogu da prodru do mozga i izazovu znatnih oštećenja. Ta jedinjenja su uglavnom hidrofobna i mala, ili imaju sposobnost inbiranja astrocitnih funkcija. Potreba da se identifikuju i tretiraju neurotoksini, je dovela do rastućeg interesovanja u neurotoksikološka istraživanja i klinička ispitivanja.^[23] Mada je klinička neurotoksikologija uglavnom u začeću, progres je napravljen u identifikaciji niza neurotoksina iz životne sredine, i klasifikacije 750 do 1000 poznatih potencijalno neurotoksičnih jedinjenja.^[20] Usled kritične važnosti nalaženja neurotoksina u životnoj sredini, razvijeni su specifični protokoli za testiranje i određivanje neurotoksičnog dejstva jedinjenja (USEPA 1998). Dodatno, in-vitro sistemi se primenjuju u sve većoj meri, jer oni imaju niz prednosti u odnosu na in-vivo sisteme, koji su ranije prvenstveno korišteni. Primeri poboljšanja su prilagodljivo, uniformno okruženje, i eliminacija kontaminarajućih efekata sistemskog metabolizma.^[23] In-vitro sistemi imaju niz ograničenja, kao što su poteškoće u adekvatnom reprodukovanju kompleksnosti nervnog sistema, poput interakcija između astrocita i neurona u formiranju BBB.^[24] Faktor koji dodatno komplikuje proces određivanja neurotoksina putem in-vitro testiranja je problem razlikovanja neurotoksičnosti i citotoksičnosti, pošto direktno izlaganje neurona datom jedinjenju nije uvek moguće in-vivo. Isto tako, ćelijski respons na hemikalije ne daje uvek preciznu indikaciju tipa toksina, pošto simptomi kao što je oksidativni stres ili skeletalne modifikacije mogu da budu posledica neurotoksičnog ali i citotoksičnog dejstva.^[25]

Da bi se prevazišle te komplikacije, nedavno je predloženo da je tačnija mera razlike između neurotoksina i citotoksina u in-vitro uslovima praćenje neuritskih izdanaka (bilo aksonskih ili dendritskih). Znatan stepen nepreciznosti ovih merenja je razlog za njihovo sporo prihvatanje širokoj upotrebi.^[26] Pored ovoga, biohemijski mehanizmi su ušli u širu primenu u neurotoksinskom testiranju, tako da je moguće testirati da li jedinjenja ometaju ćelijske mehanizme, kao što je inhibicija acetilholinesterazne sposobnosti organofosfatima (uključujući DDT i sarin gas).^[27] Mada je metodima za određivanje neurotoksičnosti još uvek potreban znatan razvoj, identifikacija simptoma izlaganja štetnim jedinjenjima i toksinima je doživela znatan napredak.

Primena u neuronauci

Mada su raznovrsni u pogledu hemijskih svojstava i funkcija, neurotoksini imaju zajedničko svojstvo da deluju istim mehanizmom, koji dovodi do poremećaja ili uništavanja neophodnih komponenti nervnog sistema. Neurotoksini su veoma korisni u polju neuronauke. Kako je nervni sistem većine organizama veoma kompleksan i neophodan za opstanak, on je prirodno postao meta napada predatora i plena. Pošto venumski organizmi često koriste svoje neurotoksine da brzo potčine predatora ili plen, toksini su evoluirali tako da su postali visoko specifični za njihove ciljne kanale, te se toksin lako ne vezuje za druge mete.^[28] Usled toga, neurotoksini su efektivna sredstva koja precizno deluju na pojedine elemente nervnog sistema. Jedan ran primer neurotoksinskog delovanja je koristio radioobleženi tetrodotoksin za isptivanje natrijumovih kanala i za precizno merenje njihove koncentracije duž nervnih membrana.^[28] Slično tome putem izolacije pojedinih aktivnosti kanala, neurotoksini su omogućili poboljšanje originalnog Hodgkin-Haklijevog modela neurona zasnovanog na teoretskoj pretpostavci da generički natrijumski ili kalijumski kanali mogu da budu odgovorni za većinu funkcija nervnog tkiva.^[28] Počevši od te preliminarne pretpostavke, koristeći opšta jedinjenja kao što su tetrodotoksin, tetraetilamonijum, i bungarotoksine došto je do razvoja znatno dubljeg rezumevanja različitih načina na koji se pojedinačni neuroni ponašaju.

Reference

^ Sivonen K (1999)
^ Scottish Government 2011
^ ^а ^б Spencer 2000
^ ^а ^б Olney 2002
^ ^а ^б ^в Kiernan 2005
^ Lidsky 2003.
^ ^а ^б Heaton 2000
^ Choi 1987
^ Zhang 1994.
^ Rosales 1996
^ Simpson 1986
^ Arnon 2001
^ Dikranian 2001
^ Deng 2003
^ Jevtovic-Todorovic 2003
^ Nadler 1978.
^ Thyagarajan 2009
^ Takadera 1990
^ Hodge 2002.
^ ^а ^б Dobbs 2009
^ ^а ^б ^в Widmaier 2008
^ ^а ^б Martini 2009
^ ^а ^б Costa 2011
^ Harry 1998.
^ Gartlon 2006.
^ Mundy 2008.
^ Lotti 2005.
^ ^а ^б ^в Adams 2003

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