Neuroprotektivna aktivnost reaktivatora kolinesteraza pri trovanju organofosfornim spojevima

doctoral thesis

• Title (english): Neuroprotective activity of cholinesterase reactivators in organophosphate poisoning
• Author: Dora Kolić
• Mentor: Zrinka Kovarik (mentor)
• Committee member: Jasmina Rokov Plavec (predsjednik povjerenstva)
• Committee member: Svjetlana Kalanj-Bognar (član povjerenstva)
• Committee member: Dubravka Švob Štrac (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2024-09-12, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Kationski piridinijevi oksimi koriste se kao reaktivatori inhibiranih enzima acetilkolinesteraze (AChE) i butirilkolinesteraze (BChE) pri liječenju trovanja organofosfornim (OP) živčanim bojnim otrovima i pesticidima. Međutim, neučinkoviti su za reaktivaciju sinaptičke AChE u mozgu zbog otežanog prolaska kationa kroz krvno-moždanu barijeru, što može potaknuti neuroupalu i trajno oštetiti moždane funkcije. Cilj ovog istraživanja bio je ispitivanje neuroprotektivnog potencijala triju novosintetiziranih skupina oksima s obzirom na poboljšane fizikalno-kemijske karakteristike u odnosu na piridinijeve oksime. Od osam oksima kationske imidazolijeve skupine, 1,3-dibenzil-2-((hidroksiimino)metil)imidazolijev bromid pokazao se učinkovitim reaktivatorom fosfilirane BChE s kojom je kao pseudokatalitički par u ex vivo uvjetima unutar 5 minuta vratio 60 % enzimske aktivnosti, što ga čini izvrsnim kandidatom za razgradnju OP spojeva u cirkulaciji prije nego dođu do ciljnih tkiva. Također, tri zwitterionska acetamidna bis-oksima na modelu miša pokazala su bolji zaštitni indeks i manju akutnu toksičnost od standardnih oksima. Terapija jednim od bis-oksima vratila je oko 70 % aktivnosti inhibirane AChE u mozgu i značajno je smanjila ekspresiju neuroupalnih biljega astroglioze i mikroglioze. Analizirani bis-oksimi imaju kapacitet sprječavanja aktivacije neuroupalnih procesa i pokazuju perspektivna fizikalno-kemijska svojstva za razvoj poboljšane terapije u slučaju trovanja OP spojevima.

Abstract (english)

Cationic pyridinium oximes are used as reactivators of inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the treatment of poisoning with organophosphorus (OP) nerve agents and pesticides. However, they are ineffective in reactivating synaptic AChE in the brain due to the difficulty of cation passage through the blood-brain barrier, which can induce neuroinflammation and permanently damage brain functions. The goal of this research was determining the neuroprotective potential of three newly synthesized oxime groups with regard to improved physicochemical characteristics compared to pyridinium oximes. Out of the eight cationic imidazolium oximes,
1,3-dibenzyl-2-((hydroxyimino)methyl)imidazolium bromide proved to be an effective ex vivo reactivator of phosphorylated BChE and as a pseudocatalytic pair it restored 60 % of the enzyme activity with a 10-fold excess cyclosarin, which makes it an excellent candidate for the degradation of OP compounds in the circulation before they reach the target tissues. Three zwitterionic acetamide bis-oximes showed a better protective index and less acute toxicity than standard oximes in a mouse model. Therapy with one of the bis- oximes restored about 70 % of the inhibited AChE in the brain and significantly reduced the expression of neuroinflammatory markers of astrogliosis and microgliosis. The analyzed bis- oximes have the capacity to prevent the activation of neuroinflammation and show promising physicochemical properties for the improvement of therapy in case of OP poisoning.

• Keywords: živčani bojni otrovi; pesticidi; krvno-moždana barijera; oksim; neuroupala; biološka čistila
• Keywords (english): nerve warfare agents; pesticides; blood-brain barrier; oxime; neuroinflammation; bioscavengers
• Language: croatian
• URN:NBN: urn:nbn:hr:217:513566
• Promotion: 2024
• Study programme: Title: Doctoral study; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica u području prirodnih znanosti (doktor/doktorica u području prirodnih znanosti)
• Type of resource: Text
• Extent: XXII, 148 str. ; 30 cm
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2026-09-12
• Created on: 2024-10-29 14:35:05