RESUMEN
(1) Huperzine A, a promising therapeutic agent for Alzheimer's disease (AD), was tested for its effects on cholinergic and monoaminergic dysfunction induced by injecting beta-amyloid peptide-(1-40) into nucleus basalis magnocellularis of the rat. (2) Bilateral injection of 10 microg beta-amyloid peptide-(1-40) into nucleus basalis magnocellularis produced local deposits of amyloid plaque and functional abnormalities detected by microdialysis. In medial prefrontal cortex, reductions in the basal levels and stimulated release of acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine were observed. However, oral huperzine A (0.18 mg/kg, once daily for 21 consecutive days) markedly reduced morphologic abnormalities at the injection site in rats infused with beta-amyloid peptide-(1-40). Likewise, this treatment ameliorated the beta-amyloid peptide-(1-40)-induced deficits in extracellular acetylcholine, dopamine, and norepinephrine (though not 5-hydroxytryptamine) in medial prefrontal cortex, and lessened the reduction in nicotine or methoctramine-stimulated release of acetylcholine and K(+)-evoked releases of acetylcholine and dopamine. (3) The present results provide the first direct evidence that huperzine A acts to oppose neurotoxic effects of beta-amyloid peptide on cholinergic, dopaminergic, and noradrenergic systems of the rat forebrain.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Núcleo Basal de Meynert/fisiopatología , Monoaminas Biogénicas/metabolismo , Colina/metabolismo , Péptidos/toxicidad , Sesquiterpenos/farmacología , Acetilcolina/metabolismo , Alcaloides , Péptidos beta-Amiloides/administración & dosificación , Animales , Núcleo Basal de Meynert/efectos de los fármacos , Núcleo Basal de Meynert/patología , Dopamina/metabolismo , Inyecciones , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Péptidos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Ratas , Ratas Sprague-Dawley , Sesquiterpenos/administración & dosificaciónRESUMEN
AIM: To assess the effects of cholinesterase inhibitors huperzine A, donepezil and rivastigmine on cerebral neurotransmitters in the cortex and hippocampus in freely-moving rats. METHODS: Double-probe cerebral microdialysis and HPLC with electrochemical detection were used to detect neurotransmitters. RESULTS: Our results showed that huperzine A (0.25, 0.5, and 0.75 micromol/kg, po) dose-dependently elevated extracellular acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and hippocampus. Oral administration of donepezil (5.4 micromol/kg) or rivastigmine (1 micromol/kg) also elicited significant increases in ACh in the mPFC and hippocampus. The time course of cortical acetylcholinesterase (AChE) inhibition with the 3 inhibitors mirrored the increases of ACh at the same dose. The marked elevation of ACh after oral administration of huperzine A (0.5 micromol/kg) and donepezil (5.4 micromol/kg) was associated with a significantly increased release of dopamine (DA) in the mPFC or hippocampus. None of the 3 inhibitors affected norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels in the mPFC and hippocampus. The effects of huperzine A and rivastigmine did not depend on the route of administration, but donepezil was less efficacious by the oral route than by ip injection. The ability of huperzine A to increase ACh levels was unchanged when tests were performed after multiple oral administration of the drug at 0.5 micromol/kg, once per day for 30 d. CONCLUSION: The present findings showed that, in molar terms, huperzine A had similar potency on increasing mPFC ACh and DA levels as compared to the 11- and 2-fold dosages of donepezil and rivastigmine, respectively, and had longer lasting effects after oral dosing.
Asunto(s)
Acetilcolina/metabolismo , Encéfalo/metabolismo , Indanos/farmacología , Fenilcarbamatos/farmacología , Piperidinas/farmacología , Sesquiterpenos/farmacología , Administración Oral , Alcaloides , Animales , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacología , Donepezilo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Indanos/administración & dosificación , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Norepinefrina/metabolismo , Fenilcarbamatos/administración & dosificación , Piperidinas/administración & dosificación , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Rivastigmina , Serotonina/metabolismo , Sesquiterpenos/administración & dosificaciónRESUMEN
The cholinesterase inhibitors huperzine A, donepezil and rivastigmine were compared for their effects on extracellular acetylcholine concentration and acetylcholinesterase activity in the rat cortex. After i.p. injection, huperzine A (0.25-0.75 micromol/kg), donepezil (2-6 micromol/kg) and rivastigmine (0.75-1.5 micromol/kg) dose-dependently elevated the concentration of acetylcholine. The duration of huperzine A was longest. The time courses of cortical acetylcholinesterase inhibition with middle doses of these agents mirrored the increases of acetylcholine at the same doses. However, acetylcholinesterase inhibition was disproportionately greater after middle dose of rivastigmine than doses of huperzine A and donepezil that increased acetylcholine to a similar extent. Muscle fasciculation appeared only after donepezil with a dose-dependent incidence and intensity. In molar terms, huperzine A was 8- and 2-fold more potent than donepezil and rivastigmine, respectively, in increasing cortical acetylcholine levels, with a longer-lasting effect.
Asunto(s)
Acetilcolina/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Carbamatos/farmacología , Corteza Cerebral/efectos de los fármacos , Indanos/farmacología , Fenilcarbamatos , Piperidinas/farmacología , Sesquiterpenos/farmacología , Acetilcolinesterasa/metabolismo , Alcaloides , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/fisiopatología , Animales , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Carbamatos/uso terapéutico , Corteza Cerebral/enzimología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo , Relación Dosis-Respuesta a Droga , Fasciculación/inducido químicamente , Fasciculación/fisiopatología , Indanos/uso terapéutico , Masculino , Neuronas/efectos de los fármacos , Neuronas/enzimología , Piperidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Rivastigmina , Sesquiterpenos/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
Recently, the potent cholinesterase inhibitor (-)-huperzine A (HupA) was demonstrated to protect neuronal and glial cells against the cytotoxicity of beta-amyloid (Abeta). Since the unnatural (+)-HupA is a much less potent inhibitor, it was of interest to examine the stereoselectivity of cellular protection by the two isomers. In the present study, effects of (+)- and (-)-HupA on Abeta(25-35)-induced injury were compared in PC12 and NG108-15 neuroblastoma cell lines. Following a 24 h exposure to 1 microM Abeta(25-35), cell survival was markedly reduced, but preincubation with (+)-HupA or (-)-HupA (0.1-10 microM) enhanced survival significantly. The potency of (-)-HupA and (+)-HupA in protecting against Abeta toxicity was similar. This result contrasted with the stereoselectivity of cholinesterase inhibition in vitro and in vivo, in which (-)-HupA is about 50-fold more potent than (+)-HupA. It is concluded that the neuroprotective properties of HupA enantiomers have no relation to anti-cholinesterase activity.