Molecular Insights Rau Cov txiaj ntsig ntawm Nicotine Ntawm Kev Nco Thiab Kev Paub (Tshawb Xyuas)
Mar 22, 2023
Abstract
Cov kev pheej hmoo ntawm kev noj qab haus huv ntawm nicotine paub zoo, tab sis muaj qee cov pov thawj ntawm nws cov txiaj ntsig zoo ntawm kev paub txog kev ua haujlwm. Qhov kev tshuaj xyuas tam sim no tau tsom mus rau cov txiaj ntsig tau tshaj tawm ntawm nicotine hauv lub hlwb thiab nthuav tawm cov txheej txheem cuam tshuam. Kev tswj hwm Nicotine tuaj yeem txhim kho kev paub tsis zoo hauv Alzheimer's disease (AD), thiab dyskinesia thiab kev nco tsis zoo hauv Parkinson's disease (PD). Nyob rau hauv cov nqe lus ntawm nws cov txheej txheem ntawm kev ua, nicotine slows txoj kev loj hlob ntawm PD los ntawm inhibiting Sirtuin 6, ib tug stress-responsive protein deacetylase, yog li txo neuronal apoptosis thiab txhim kho neuronal ciaj sia taus.
Nyem xyuas seb cistanche siv rau dab tsi
Hauv AD, nicotine txhim kho kev paub tsis meej los ntawm kev txhim kho cov protein kinase B (tseem hu ua Akt) kev ua haujlwm thiab txhawb nqa phosphoinositide 3-kinase / Akt signaling, uas tswj cov txheej txheem kev kawm thiab kev nco. Nicotine kuj tseem tuaj yeem qhib cov thyroid receptor signaling txoj hauv kev los txhim kho kev nco tsis zoo los ntawm hypothyroidism. Hauv cov tib neeg noj qab haus huv, nicotine txhim kho kev nco tsis zoo los ntawm kev pw tsaug zog los ntawm kev txhim kho cov phosphorylation ntawm calmodulin-dependent protein kinase II, ib qho tseem ceeb regulator ntawm cell proliferation thiab synaptic plasticity.
Tsis tas li ntawd, nicotine tuaj yeem txhim kho kev nco qab los ntawm nws cov txiaj ntsig ntawm kev hloov pauv ntawm chromatin los ntawm inhibition ntawm histone deacetylases, uas ua rau muaj kev hloov pauv hauv kev nco txog cov noob. Thaum kawg, kev tswj hwm nicotine tau pom tias yuav cawm tau lub sijhawm ntev rau cov neeg uas pw tsaug zog, AD, kev ntxhov siab ntev, thiab hypothyroidism, feem ntau los ntawm desensitizing 7 nicotinic acetylcholine receptors. Los xaus, nicotine muaj ntau yam kev paub txog kev noj qab haus huv rau cov tib neeg, nrog rau cov neeg muaj kev paub tsis meej nrog ntau yam kab mob. Txawm li cas los xij, kev tshawb fawb ntxiv yog xav tau los ua kom pom kev cuam tshuam ntawm kev kho mob nicotine mob thiab mob ntev ntawm kev nco ua haujlwm.
1. Taw qhia
Nicotine, los yog 3-(1-Methylpyrrolidin-2-yl) pyridine, yog ib qho alkaloid uas muaj nyob hauv cov nroj tsuag luam yeeb (1,2). Kev siv cov tshuaj nicotine tuaj yeem ua rau muaj ntau yam teeb meem kev noj qab haus huv, suav nrog kab mob plawv thiab ntsws, thiab ua rau muaj kev pheej hmoo ntawm kev mob qog noj ntshav (3) thiab ua rau muaj kev cuam tshuam rau ntau yam kab mob, suav nrog tuberculosis, mob ntsws, thiab kab mob sib deev xws li chlamydia (4). Txawm li cas los xij, cov pov thawj nce ntxiv qhia tias nicotine tseem muaj txiaj ntsig zoo rau kev noj qab haus huv, tshwj xeeb yog hais txog kev paub txog kev ua haujlwm. Nicotine ua raws li agonist ntawm nicotinic cholinergic receptors (nAChRs), uas muaj nyob rau hauv ob qho tib si hauv nruab nrab paj hlwb (CNS) thiab lub paj hlwb peripheral (2,5,6). Txhua nAChR muaj tsib lossis subunits (7). Muaj cuaj lub peev xwm subunits thiab peb subunits, thiab cov nAChR receptor subtypes sib txawv muaj qhov sib txawv ntawm cov subunits (8,9). Qhov ntau tshaj receptor subtypes tam sim no nyob rau hauv tib neeg lub hlwb yog 4 2, 3 4 (heterogenic), thiab 7 (homomeric) (10).
Lub 3 4 nAChR paub los kho cov kab mob plawv ntawm nicotine (11), thaum homomeric 7 nAChR tau xav tias yuav koom nrog hauv kev sib kis, nrog rau kev kawm thiab kev nkag siab (12,13). Kev txhawb nqa ntawm nAChRs hauv CNS los ntawm nicotine lossis acetylcholine tswj kev tso tawm ntau yam neurotransmitters, xws li dopamine, glutamate, serotonin, norepinephrine, thiab -aminobutyric acid (14,15). Yog li ntawd, kev hloov pauv hauv kev qhia lossis kev ua haujlwm ntawm nAChRs, vim muaj kab mob, tuaj yeem hloov pauv kev tso tawm ntawm lwm cov neurotransmitters thiab, yog li, cuam tshuam rau lub hlwb ua haujlwm. Nws feem ntau paub tias kev raug nicotine mus ntev ua rau nAChR desensitization (16), ua rau kev nco tsis zoo rau lwm tus neeg noj qab haus huv (17). Xws li nicotine-induced kev paub tsis meej yog txuam nrog ntau lub tswv yim, nrog rau kev ua kom cov phosphodiesterase-5 (PDE-5) qhia txoj hauv kev thiab inhibition ntawm estrogen biosynthesis (18,19). Tshwj xeeb, nicotine txhawb nqa qhov kev qhia ntawm PDE-5 (19,20), uas ua lub luag haujlwm hauv kev tshem tawm cyclic guanosine monophosphate thiab cyclic adenosine monophosphate uas ua rau cov kev taw qhia hauv qab uas ua rau muaj kev puas tsuaj rau kev nco (21-23).
Nicotine tseem thaiv cov tshuaj estrogen synthase (aromatase) hauv lub hlwb, uas yog ib qho tseem ceeb rau estrogen biosynthesis (18,24). Estrogen activates estrogen receptors nyob rau hauv lub hlwb, uas ua hauj lwm raws li transcriptional yam tseem ceeb thiab txhim khu kev qhia ntawm ntau neurotransmitters (xws li glutamate, acetylcholine, serotonin, thiab noradrenaline), thiab yog li txhawb lub neuronal circuits uas yuav tsum tau rau kev nco encoding (25). Yog li, kev hloov pauv hauv cov tshuaj estrogen biosynthesis vim nicotine (20,26), nrog rau kev nce siab ntawm nicotine-induced ntawm PDE-5, tuaj yeem ua rau muaj kev puas hlwb hauv cov neeg noj qab haus huv. Nyob rau hauv sib piv rau cov kev puas tsuaj ntawm nicotine ntawm kev txawj ntse muaj nuj nqi, qee cov kev tshawb fawb qhia tias nicotine kuj muaj txiaj ntsig zoo rau kev nco thiab kev kawm. Yog li, qhov kev tshuaj xyuas tam sim no qhia txog cov txiaj ntsig zoo ntawm nicotine ntawm kev paub (Daim duab 1).
2. Cov txiaj ntsig ntawm nicotine hauv Alzheimer's disease (AD)
AD yog kab mob neurodegenerative uas feem ntau cuam tshuam rau cov neeg laus thiab ua rau dementia (27). AD yog tus cwj pwm los ntawm kev tso tawm ntawm cov tshuaj lom amyloid- (A) thiab tau cov proteins hauv lub hlwb (28,29). Tshwj xeeb, qhov sib txuam ntawm A tau pom tias inhibit mitochondrial muaj nuj nqi, ua rau muaj kev ua kom muaj pa oxygen ntau ntxiv thiab ua rau cov txheej txheem inflammatory (30). Tseeb, ntau qhov kev tshawb fawb tau qhia tias A deposition hloov lub physiological muaj nuj nqi ntawm lub hlwb thiab ua rau neuronal dysfunction (31,32). Hmoov tsis zoo, tseem tsis tau muaj kev kho mob rau AD, thiab tam sim no tus kab mob tau tswj hwm los ntawm kev ua kom qeeb qeeb nrog kev tswj hwm cov tshuaj antioxidants thiab tshuaj xws li cholinesterase inhibitors (33). Raws li cholinergic hypothesis, kev paub txog kev poob qis hauv AD tshwm sim los ntawm qhov tsis txaus hauv nruab nrab cholinergic neurotransmission vim qhov poob ntawm acetylcholine (34). Yog li ntawd, cholinesterase inhibitors (xws li donepezil thiab galantamine), uas thaiv kev degradation ntawm acetylcholine, tseem yog thawj txoj hauv kev los kho cov haujlwm hauv nruab nrab cholinergic hauv AD.
Ntxiv mus, kev hloov pauv hauv kev qhia thiab qhov ceev ntawm 7 nAChRs hauv hippocampus tau pom nyob rau hauv AD thiab pom tias muaj feem cuam tshuam rau kev txawj ntse (35). Xws li 7 nAChRs kuj tau pom tias muaj kev sib koom ua ke nrog cov plaques hauv AD (36). Yog li, agonists ntawm 7 nAChRs, suav nrog nicotine, tej zaum yuav pab tau rau kev kho AD. Qhov stimulation ntawm nAChRs los ntawm nicotine kuj yuav cuam tshuam rau downstream signaling molecules, nrog rau cov protein kinases, uas yog ib qho tseem ceeb regulators ntawm synaptic plasticity thiab nco (37). Hauv particular, protein kinase B (tseem hu ua Akt) yog lub hauv paus molecule ntawm phosphoinositide 3-kinase (PI3K) / Akt signaling pathway, uas ua lub luag haujlwm tseem ceeb hauv kev tswj hwm kev ua haujlwm ntawm cov neurons hauv CNS, suav nrog kev muaj sia nyob ntawm neuronal ( 38–42), thiab kev kawm thiab kev nco encoding (38,43,44).
Yog li, nws yog qhov xav tias qhov kev txhawb nqa ntawm nAChRs los ntawm nicotine los yog nws cov analogs ua rau PI3K / Akt signaling txoj hauv kev, uas, nyob rau hauv lem, tswj kev kawm thiab nco cov txheej txheem (42,45). Qhov tseeb, kev tswj xyuas mob hnyav thiab mob ntev ntawm nicotine tau tshaj tawm los txhim kho kev paub tsis meej hauv cov neeg mob AD (46-48). Tsis tas li ntawd, kev tswj hwm tus mob nicotine thaum lub sij hawm electroencephalography (EEG) ua rau cov neeg mob AD uas tau txais cholinesterase inhibitors tau pom tias hloov EEG kev nyeem ntawv mus rau qib qub (49). Yog li, kev tswj hwm nicotine tuaj yeem muaj txiaj ntsig zoo rau kev paub txog kev poob qis hauv AD.
3. Cov txiaj ntsig ntawm nicotine hauv Parkinson's disease (PD)
PD yog qhov mob neurodegenerative tshaj plaws thib ob tom qab AD uas cuam tshuam rau cov neeg laus (50). Txawm hais tias qhov tseeb ntawm PD tseem tsis to taub tag nrho, nws cov kab mob cuam tshuam nrog kev poob lossis degeneration ntawm dopaminergic neurons (dopamine-producing neurons) hauv substantia nigra ntawm midbrain (51). Qhov kev poob ntawm dopaminergic neurons ua rau muaj kev cuam tshuam ntawm kev tswj lub cev muaj zog, tremors, rigidity thiab bradykinesia, thiab kev paub tsis meej (52,53). Kev tshawb fawb hauv cov qauv tsiaj ntawm PD tau qhia tias nicotine tuaj yeem tiv thaiv lub hlwb ntawm kev puas tsuaj (54,55). Kev haus luam yeeb kuj tau tshaj tawm los txo qhov kev pheej hmoo ntawm PD tshwm sim (53), thiab nicotine tuaj yeem pab txhim kho qee cov tsos mob ntawm PD, xws li dyskinesia thiab kev nco tsis zoo (55).
Tseeb tiag, cov teebmeem neuroprotective ntawm nicotine hauv PD tau raug tshuaj xyuas hauv vitro thiab hauv vivo, thiab tau pom tias feem ntau yog vim nws txoj kev muaj sia nyob ntawm dopaminergic neurons (56). Ntxiv nrog rau kev ua kom muaj txoj sia nyob hauv lub hlwb, xws li PI3K / Akt txoj hauv kev, nicotine kuj tseem tuaj yeem ua rau qeeb qhov kev loj hlob ntawm PD los ntawm inhibiting Sirtuin 6 (SIRT6), NAD ntxiv rau cov chav kawm III diacetyl-lase (57. ). Qhov kev tawm tsam ntawm SIRT6 no tau pom los txo qis apoptosis thiab nce neuron ciaj sia taus (57). Raws li qhov tshwm sim, ntau qhov kev tshawb fawb tau tshaj tawm tias qhov kev tshaj tawm ntawm SIRT6 cuam tshuam cov ntsiab lus ntawm kev ntshai kev nco (58,59). Txawm li cas los xij, lwm txoj kev tshawb fawb pom tias poob ntawm SIRT6 hauv lub hlwb kuj ua rau kev nco tsis zoo (60). Yog li ntawd, cov teebmeem hauv qab ntawm nicotine ntawm SIRT6 hauv PD xav tau kev tshawb nrhiav ntxiv.
4. Cov txiaj ntsig ntawm nicotine ntawm cov txheej txheem nco hauv cov neeg mob uas muaj kab mob thyroid
Cov kev tshawb fawb tau qhia tias cov thyroid hormones (61), suav nrog thyroxine (T4) thiab triiodothyronine (T3), tswj lub hlwb kev loj hlob, neurogenesis, synaptogenesis, thiab myelination (62,63). T3 thiab T4 yog synthesized nyob rau hauv lub thymus (64,65), tso rau hauv cov hlab ntsha, thiab nws thiaj li ua rau lawv cov teebmeem los ntawm kev khi rau ib tug nuclear receptor hu ua cov thyroid hormone receptor (TR), uas muaj nyob rau hauv ob lub isoforms sib txawv, , thiab ( 66). Cov kev qhia theem ntawm cov isoforms txawv ntawm cov ntaub so ntswg: 1 receptor yog feem ntau qhia nyob rau hauv lub plawv thiab lub cev nqaij daim tawv (67), whereas 1 mas qhia nyob rau hauv daim siab, raum, thiab hlwb (68). TRs kuj tau nthuav tawm ntau hauv hippocampus, uas yog ib feem ntawm lub hlwb uas yog lub luag haujlwm rau kev tsim lub cim xeeb (63). Yog li ntawd, nyob rau hauv cov kab mob xws li hyperthyroidism, hypothyroidism, thiab cretinism, nyob rau hauv uas txawv txav cov thyroid hormone theem (69,70), hippocampal muaj nuj nqi yuav cuam tshuam, yog li ua rau kev txawj ntse tsis zoo (71).
Tseeb, cov kev tshawb fawb neuroimaging tau pom tias cov qauv thiab kev ua haujlwm ntawm hippocampus tau hloov pauv hauv cov neeg mob hypothyroidism (72-74). Ntawm qhov kev ceeb toom, kev tswj hwm tus mob nicotine tau raug tshaj tawm kom qhib TRs (tshwj xeeb tshaj yog TR hauv lub hlwb) thiab, yog li, tuaj yeem txhim kho kev kawm thiab kev nco hauv qee tus neeg (66). Tsis tas li ntawd, TR knockout hauv nas tsis cuam tshuam rau kev nco ua haujlwm tom qab kev tswj hwm nicotine, lees paub lub luag haujlwm ntawm TR hauv cov txheej txheem nco (75). Tsis tas li ntawd, kev nco tsis zoo tshwm sim los ntawm hypothyroidism tau tshwm sim los ntawm nicotine los ntawm kev hloov kho ntawm calcineurin, uas tswj kev ua haujlwm ntawm calmodulin-dependent protein kinase II (CaMKII) los txhim kho synaptic plasticity (76). Txawm li cas los xij, cov txheej txheem meej meej ntawm kev tswj hwm nicotine hauv kev txhim kho kev paub tsis meej hauv cov neeg mob cov kab mob thyroid yuav tsum tau tshawb xyuas ntxiv.
5. Kev cuam tshuam ntawm nicotine rau kev paub txog kev ua haujlwm hauv cov neeg noj qab haus huv
Muaj cov pov thawj ntxiv tias kev tswj hwm nicotine tuaj yeem txhim kho kev nco hauv lwm tus neeg noj qab haus huv. Piv txwv li, kev tshawb fawb tau qhia tias kev pw tsaug zog ua rau kev nco tsis zoo los ntawm kev txo qis phosphorylation ntawm CaMKII, uas yog ib qho tseem ceeb regulator ntawm cell proliferation thiab synaptic plasticity (77-79). CaMKII yav dhau los tau pom los tswj cov kev qhia ntawm glutamate receptor subunit-1 thiab nws cov khoom lag luam mus rau qhov chaw synaptic, uas yog qhov tsim nyog rau kev ua haujlwm ntawm lub hlwb thiab kev tsim lub cim xeeb (80). Raws li qhov tshwm sim, kev tswj hwm nicotine raug pom los txhim kho kev nco tsis zoo los ntawm kev pw tsaug zog los ntawm kev txhim kho phosphorylation ntawm CaMKII (81). Yog li, nicotine tuaj yeem txhim kho kev nco tsis zoo los ntawm kev pw tsaug zog tsis zoo rau lwm tus neeg noj qab haus huv.
6. Nicotine-induced chromatin hloov kho tuaj yeem txhim kho kev nco thiab kev kawm
Qee qhov kev tshawb fawb tau qhia tias nicotine cuam tshuam rau chromatin hauv cell nucleus (82-84). Chromatin yog tsim los ntawm plaub subunits, hu ua histones, uas tuaj yeem hloov kho ntawm acetylation, methylation, lossis phosphorylation (85), yog li tswj cov noob hloov pauv (86,87). Hauv particular, histone acetyltransferases thiab histone deacetylases (HDACs) ua lub luag haujlwm tseem ceeb hauv kev hloov kho chromatin koom nrog ntau lub zog ntawm tes, suav nrog kev nco thiab synaptic plasticity (88,89). Piv txwv li, inhibition ntawm HDACs tuaj yeem nce qhov kev qhia ntawm cov noob tseem ceeb koom nrog hauv cov txheej txheem nco, uas yog tswj hwm los ntawm cAMP cov lus teb cov ntsiab lus-binding protein (CREB)-CREB-binding protein transcriptional complex (89).
Tshwj xeeb, HDAC4 tau pom tias yog qhov tseem ceeb rau kev kawm thiab kev nco txog (89,90). Raws li kev haus luam yeeb tau raug tshaj tawm los hloov kho cov kev cai ntawm chromatin los ntawm kev hloov pauv cov haujlwm ntawm HDACs, xws li HDAC6, hauv lub ntsws (83), nws kuj yuav muaj qhov cuam tshuam zoo sib xws hauv CNS. Tseeb, nws tau raug qhia tias nicotine tuaj yeem cuam tshuam HDACs hauv lub hlwb, thiab, yog li, txhim kho kev nco (84). Txawm li cas los xij, kev tshawb fawb ntxiv yuav tsum tau tshawb xyuas cov txiaj ntsig ntawm nicotine ntawm kev paub txog kev ua haujlwm los ntawm kev hloov pauv chromatin.
7. Electrophysiological teebmeem ntawm nicotine: Strengthening synapses
Cov neurons hauv lub hlwb sib cuam tshuam los tsim cov tes hauj lwm, uas tau teeb tsa raws li kev ua haujlwm (91). Yog li ntawd, kev nkag siab txog cov kev sib txuas no tso cai rau qee thaj chaw los txhawb thiab kaw, los saib xyuas cov tshuaj neurotransmitter tso tawm thiab cov lus teb receptor hauv qee thaj tsam ntawm lub hlwb. Long-term potentiation (LTP) yog siv los ntsuas synaptic plasticity thiab tuaj yeem muab cov qauv cellular ntawm kev kawm thiab kev nco encoding. Piv txwv li, kev nce qib ntawm glutamate tso tawm los ntawm presynaptic mus rau postsynaptic neurons tau pom los txhim kho lub peev xwm excitatory postsynaptic hauv hippocampus thaum lub sij hawm kawm spatial (92). Yav dhau los, cov kev tshawb fawb tau tshaj tawm tias mob nicotine raug cawm LTP hauv cov tib neeg uas pw tsaug zog (81).
Tsis tas li ntawd, kev tswj xyuas cov nicotine ntev tau raug qhia los txhim kho LTP hauv AD, cov qauv kev ntxhov siab ntev, thiab cov qauv hypothyroidism (74,93,94). Kuj tseem muaj cov ntaub ntawv pov thawj ntxiv tias qhov kev rov qab los ntawm LTP vim muaj cov nicotine raug cuam tshuam rau qhov normalization ntawm phosphorylation ntawm qhov tseem ceeb kinases, xws li CREB thiab CaMKIV (48,78,95). Yog li, kev tswj hwm nicotine tuaj yeem ntxiv dag zog rau cov synapses ntawm ob lub paj hlwb, ua rau kev nco zoo hauv ob tus neeg noj qab haus huv thiab cov neeg muaj kab mob xws li AD lossis hypothyroidism.
8. Cov lus xaus
Cov kev tshawb pom tau tshaj tawm hauv cov kev tshawb fawb suav nrog hauv tsab xov xwm tshuaj xyuas tam sim no qhia tias nicotine tuaj yeem txhawb kev nco ua haujlwm. Yog li ntawd, txawm hais tias nicotine zoo ib yam li lwm yam kev puas siab puas ntsws, nyob rau hauv uas nws tuaj yeem ua rau muaj kev vam khom lossis kev tsim txom, nws kuj muaj qee yam txiaj ntsig zoo, suav nrog kev txhim kho kev paub txog kev noj qab haus huv ntawm cov tib neeg noj qab haus huv thiab txhim kho kev nco ua haujlwm hauv cov neeg mob uas muaj kab mob, xws li AD, PD, thiab hypothyroidism.
Cistanche neuroprotection nyhuv
Cistanche yog ib tsob nroj extract paub txog nws cov khoom tiv thaiv neuroprotective, thiab nws cov txheej txheem ntawm kev txiav txim ntseeg tau tias muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kab mob, thiab cov teebmeem antiapoptotic. Muaj ntau qhov kev ntsuam xyuas thiab daim ntawv thov cuam tshuam txog cov teebmeem neuroprotective ntawm Cistanche, uas suav nrog:
1. Kev tshawb fawb hauv vitro: Kev tshawb fawb hauv vitro tau pom tias Cistanche extract tiv thaiv cov neurons los ntawm kev ntxhov siab vim kev puas tsuaj los ntawm kev txo qis oxidative kev nyuaj siab thiab mob.
2. Tsiaj kev tshawb fawb: Tsiaj cov kev tshawb fawb pom tau hais tias Cistanche tuaj yeem tiv thaiv kev puas tsuaj ntawm neuronal los ntawm cerebral ischemia, mob hlwb raug mob, thiab raug mob neurotoxin.
3. Tib neeg cov kev tshawb fawb: Muaj cov pov thawj tsis tshua muaj pov thawj ntawm cov teebmeem neuroprotective ntawm Cistanche hauv tib neeg, tab sis qee qhov kev tshawb fawb tau qhia tias nws tuaj yeem txhim kho kev txawj ntse thiab txo cov hnub nyoog ntsig txog kev nco.
Cov ntaub ntawv
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Department of Pharmacology thiab Toxicology, College of Pharmacy, Qassim University, Buraydah 52571, Qassim, Kingdom of Saudi Arabia
