Update on the Benefits and Mechanisms of Action of the Bioactive Vegetal Alkaloid Berberine on Lipid Metabolism and Homeostasis

Elevation of circulating levels of blood cholesterol, especially LDL cholesterol, and/or the decrease of HDL cholesterol levels have long been recognized as primary risk factors for developing atherosclerosis that leads to cardiovascular and cerebrovascular disease. Hypertriglyceridemia is an independent risk factor that is known to contribute to the development of atherosclerosis. Thus, various interventional efforts aimed at reducing hypercholesterolemia and hypertriglyceridemia have been practiced clinically for decades to reduce morbidity and mortality risk associated with deleterious cardiovascular and cerebrovascular events. As such, many drugs have been developed and clinically used to treat hypocholesteremia and/or hypertriglyceridemia; however, dietary approaches including supplements along with changes in nutrition and lifestyle have become increasingly attractive and acceptable methods used to control borderline or moderately increased levels of blood cholesterol and triacylglycerols. In this regard, the use of a plant/herbal bioactive compound, berberine (BBR), has recently been studied extensively in terms of its efficacy as well as its mechanisms of action and safety as an alternative intervention that beneficially modulates blood lipids. The aim of this review is to provide a comprehensive update on BBR research, new concepts and directions in terms of product development and current challenges, and future prospects of using BBR to manage diseases and complications associated with dyslipidemia.Peer Reviewe

17\u3b2-estradiol attenuates excitatory neurotransmission and enhances the excitability of rat parabrachial neurons in vitro

The steroid hormone 17\u3b2-estradiol and its respective receptors have been found in several cardiovascular nuclei in the central nervous system including the parabrachial nucleus. In a previous study, we provided evidence that 17\u3b2-estradiol attenuated an outward potassium conductance in parabrachial neurons of male rats, using an in vitro slice preparation. In this study we sought to enhance the comprehensive information provided previously on estradiol's postsynaptic effects in the parabrachial nucleus by directly examining whether 17\u3b2-estradiol application will modulate excitatory synaptic neurotransmission. Using a pontine slice preparation and whole-cell patch-clamp recording, bath application of either 17\u3b2-estradiol (20\u2013100 \u3bcM) or BSA-17\u3b2-estradiol (50 \u3bcM) decreased the amplitude of evoked excitatory postsynaptic currents (from 30\u201360% of control) recorded from neurons in the parabrachial nucleus. The paired pulse ratio was not significantly affected and suggests a post-synaptic site of action. The inhibitory effect on the synaptic current was relatively long-lasting (non-reversible) and was blocked by the selective estrogen receptor antagonist, ICI 182,780. Furthermore, 17\u3b2-estradiol reduced the maximum current elicited by a ramp protocol, increased the input resistance measured between resting membrane potential and action potential threshold and caused an increase in the firing frequency of the cells under current-clamp. In summary, 17\u3b2-estradiol caused 3 effects: first, a depolarization; second, a reduction in evoked excitatory postsynaptic potentials; and third, an enhancement of action potential firing frequency in neurons of the parabrachial nucleus. These observations are consistent with our previous findings and support a role for estrogen in modulating neurotransmission in this nucleus.Peer reviewed: YesNRC publication: Ye

Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of na\uefve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 \ub1 85.9% (n = 5) which further increased by 733.1 \ub1 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 \ub1 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP5\u201311 (10\u2013100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from na\uefve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in na\uefve rats, cocaine\u2019s effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine\u2019s effects are mimicked by SP.Peer reviewed: YesNRC publication: Ye

A novel method for inducing focal ischemia in vitro

Current in vitro models of stroke involve applying oxygen-glucose deprived (OGD) media over an entire brain slice or plate of cultured neurons. Thus, these models fail to mimic the focal nature of stroke as observed clinically and with in vivo rodent models of stroke. Our aim was to develop a novel in vitro brain slice model of stroke that would mimic focal ischemia and thus allow for the investigation of events occurring in the penumbra. This was accomplished by focally applying OGD medium to a small portion of a brain slice while bathing the remainder of the slice with normal oxygenated media. This technique produced a focal infarct on the brain slice that increased as a function of time. Electrophysiological recordings made within the flow of the OGD solution (\u201ccore\u201d) revealed that neurons rapidly depolarized (anoxic depolarization; AD) in a manner similar to that observed in other stroke models. Edaravone, a known neuroprotectant, significantly delayed this onset of AD. Electrophysiological recordings made outside the flow of the OGD solution (\u201cpenumbra\u201d) revealed that neurons within this region progressively depolarized throughout the 75 min of OGD application. Edaravone attenuated this depolarization and doubled neuronal survival. Finally, synaptic transmission in the penumbra was abolished within 50 min of focal OGD application. These results suggest that this in vitro model mimics events that occur during focal ischemia in vivo and can be used to determine the efficacy of therapeutics that target neuronal survival in the core and/or penumbra.Actuellement, les mod\ue8les in vitro d\u2019AVC consistent \ue0 appliquer un milieu d\ue9pourvu d\u2019oxyg\ue8ne et de glucose sur une tranche enti\ue8re de cerveau ou une plaque de neurones en culture. Toutefois, ces mod\ue8les ne parviennent pas \ue0 imiter la nature focale de l\u2019AVC comme on l\u2019observe sur le plan clinique et dans les mod\ue8les d\u2019AVC in vivo de rongeurs. Notre objectif \ue9tait donc de mettre au point un mod\ue8le in vitro in\ue9dit de tranche de cerveau qui imiterait l\u2019isch\ue9mie focale, permettant ainsi d\u2019\ue9tudier ce qui se produit dans la r\ue9gion de la p\ue9nombre. Pour ce faire, nous avons appliqu\ue9 localement, sur une petite portion de la tranche de cerveau, du milieu d\ue9pourvu d\u2019oxyg\ue8ne et de glucose, tandis que le reste de la tranche reposait dans un milieu oxyg\ue9n\ue9 normal. Cette technique produit un infarctus focal sur la tranche de cerveau qui s\u2019\ue9tend en fonction du temps. Des enregistrements \ue9lectrophysiologiques effectu\ue9s dans le flux de la solution d\ue9pourvue d\u2019oxyg\ue8ne et de glucose (centre de l\u2019aire infarcie) ont r\ue9v\ue9l\ue9 que les neurones se d\ue9polarisent rapidement (d\ue9polarisation anoxique), de fa\ue7on similaire \ue0 d\u2019autres mod\ue8les d\u2019AVC. L\u2019\ue9daravone, un agent neuroprotecteur connu, a retard\ue9 de mani\ue8re importante l\u2019apparition de cette d\ue9polarisation anoxique. Les enregistrements \ue9lectrophysiologiques effectu\ue9s hors du flux de solution d\ue9pourvue d\u2019oxyg\ue8ne et de glucose (p\ue9nombre) ont r\ue9v\ue9l\ue9 que les neurones de cette r\ue9gion se d\ue9polarisent progressivement au cours des 75 minutes d\u2019application du milieu d\ue9pourvu d\u2019oxyg\ue8ne et de glucose. L\u2019\ue9daravone a att\ue9nu\ue9 cette d\ue9polarisation et a am\ue9lior\ue9 du double la survie des neurones. Enfin, la transmission synaptique dans la p\ue9nombre a disparu dans les 50 minutes qui ont suivi l\u2019application locale du milieu d\ue9pourvu d\u2019oxyg\ue8ne et de glucose. D\u2019apr\ue8s les r\ue9sultats obtenus, ce mod\ue8le in vitro imite ce qui se produit au cours d\u2019une isch\ue9mie focale in vivo et il est possible de l\u2019utiliser pour v\ue9rifier l\u2019efficacit\ue9 de traitements qui visent la survie des neurones dans le centre et la p\ue9nombre d\u2019une aire infarcie.Peer reviewed: YesNRC publication: Ye

Ethyl-eicosapentaenoate modulates changes in neurochemistry and brain lipids induced by parkinsonian neurotoxin 1-methyl-4-phenylpyridinium in mouse brain slices

Evidence suggests a link between Parkinson's disease and the dietary intake of omega (n) 123 and n 126 polyunsaturated fatty acids (PUFAs). Presently, we investigated whether an acute dose of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) affects brain n 123 and n 126 PUFA content and expression of fatty acid metabolic enzymes cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) in brain slices from C57Bl/6mice. Furthermore, we investigated whether feeding a diet of n 123 PUFA ethyl-eicosapentaenoate (E-EPA) to these mice can attenuate the MPP+ induced changes in brain PUFA content and expression of cPLA2 and COX-2, and attenuate MPP+ induced changes in neurotransmitters and metabolites and apoptotic markers, bax, bcl-2 and caspase-3. MPP+ increased brain content of n 126 PUFAs linoleic acid and arachidonic acid, and increased the mRNA expression of cPLA2. MPP+ also depleted striatal dopamine levels and increased dopamine turnover, and depleted noradrenaline levels in the frontal cortex. The neurotoxin induced increases in bax, bcl-2 and caspase-3 mRNA expression that approached significance. E-EPA by itself increased brain n 123 content, including EPA and docosapentaenoic acid (C22:5, n 123), and increased cortical dopamine. More importantly, E-EPA attenuated the MPP+ induced increase in n 126 fatty acids content, partially attenuated the striatal dopaminergic turnover, and prevented the increases of pro-apoptotic bax and caspase-3 mRNAs. In conclusion, increases in n 126 PUFAs in the acute stage of exposure to parkinsonian neurotoxins may promote pro-inflammatory conditions. EPA may provide modest beneficial effects in Parkinson's disease, but further investigation is warranted.Peer reviewed: YesNRC publication: Ye

Substance P and cocaine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro

Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine-like effects that are known to be D1-receptor-mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another.Wereport here that SP and SP5\u201311 actions occlude the effect of cocaine and vice versa. SP, SP5\u201311 and cocaine all depressed evoked, non-N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents in a concentration-dependent manner, with EC50 values of 0.12, 0.17 and 8.3 lm, respectively. Although cocaine was the least potent, it was most efficacious. SP, SP5\u201311 and cocaine all suppressed isolated NMDA receptor-mediated evoked EPSCs. SP5\u201311 (1 lm)-induced EPSC depression was blocked by the neurokinin-1 antagonist L732138 and by the D1-like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 lm) depressed the EPSC by 39.1% \ub1 4.8%. Application of SP or SP5\u201311 (1 lm) at the peak of the cocaine depressive effect on theEPSCdid not produce any additional diminution of the response (5.7% \ub1 2.8%). In the reverse experiments, in which either SP or SP5\u201311 was applied first, subsequent application of cocaine at the peak of the peptide\u2019s effect (30.3% \ub1 2.3%) produced a further but smaller depression (15.5% \ub1 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.On a observ\ue9 que la substance P (SP) avait des effets semblables \ue0 ceux de la coca\uefne sur la transmission synaptique excitatrice dans le noyau accumbens (NAc). Afin de d\ue9terminer si la SP agit comme un m\ue9diateur endog\ue8ne et a des effets semblables \ue0 ceux de la coca\uefne, dont on sait qu\u2019ils sont m\ue9di\ue9s par les r\ue9cepteurs dopaminergiques D1, nous avons cherch\ue9 \ue0 v\ue9rifier l\u2019hypoth\ue8se selon laquelle la SP bloque les effets de la coca\uefne sur les courants postsynaptiques excitateurs dans le NAc, et vice versa. Nous avons observ\ue9 dans le cadre de nos travaux que la SP et le peptide SP5\u201311 bloquent l\u2019effet de la coca\uefne, et inversement. La SP, le peptide SP5\u201311 et la coca\uefne ont tous provoqu\ue9 une d\ue9pression des courants synaptiques \ue9voqu\ue9s m\ue9di\ue9s par des r\ue9cepteurs non NMDA (N-m\ue9thyl-D-aspartate), effet qui \ue9tait fonction de la concentration; les CE50 \ue9taient de 0,12, 0,17 et 8,3 \u3bcm, respectivement. Bien que la coca\uefne ait \ue9t\ue9 la moins active de ces substances, elle s\u2019est r\ue9v\ue9l\ue9e \ueatre la plus efficace. La SP, le peptide SP5\u201311 et la coca\uefne ont tous les trois supprim\ue9 des courants postsynaptiques excitateurs isol\ue9s \ue9voqu\ue9s par des r\ue9cepteurs NMDA. La d\ue9pression des courants postsynaptiques excitateurs induite par le peptide SP5\u201311 (1 \u3bcm) a \ue9t\ue9 bloqu\ue9e par la mol\ue9cule L732138, un antagoniste de la neurokinine-1, et par la mol\ue9cule SCH23390, un antagoniste des r\ue9cepteurs de type D1. Le pr\ue9traitement des coupes par la coca\uefne (30 \u3bcm) a d\ue9prim\ue9 le courant postsynaptique excitateur de 39,1 % \ub1 4,8 %. L\u2019application de la SP ou du peptide SP5\u201311 (1 \u3bcm) au moment o\uf9 l\u2019effet d\ue9pressif de la coca\uefne sur le courant postsynaptique excitateur \ue9tait \ue0 son maximum n\u2019a provoqu\ue9 aucune diminution additionnelle de la r\ue9ponse (5,7 % \ub1 2,8 %). Dans les exp\ue9riences inverses, o\uf9 l\u2019on appliquait d\u2019abord la SP ou le peptide SP5\u201311, l\u2019application de la coca\uefne au moment o\uf9 l\u2019effet de la SP ou du peptide \ue9tait \ue0 son maximum (30,3 % \ub1 2,3 %) a entra\ueen\ue9 une d\ue9pression additionnelle, quoique l\ue9g\ue8re (15,5 % \ub1 3,6 %), du courant postsynaptique excitateur restant. Selon ces donn\ue9es, la coca\uefne et la SP ont un effet similaire sur la transmission synaptique excitatrice dans le NAc et se bloquent mutuellement. Ceci donne \ue0 penser que la SP peut agir comme la coca\uefne en l\u2019absence de celle-ci et servir de d\ue9clencheur endog\ue8ne du circuit de la r\ue9compense et des comportements associ\ue9s \ue0 la coca\uefne.Peer reviewed: YesNRC publication: Ye

Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 ± 85.9% (n = 5) which further increased by 733.1 ± 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 ± 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP5–11 (10–100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine’s effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine’s effects are mimicked by SP. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’