Conessine

Conessine, an H3 receptor antagonist, alters behavioral and neurochemical effects of ethanol in mice.[Pubmed:26924015]

Behav Brain Res. 2016 May 15;305:100-7.

Ethanol abuse potential is mainly due to its reinforcing properties, crucial in the transition from the recreational to pathological use. These properties are mediated by mesocorticolimbic and nigrostriatal dopaminergic pathways and neuroadaptations in these pathways seem to be responsible for addiction. Both pathways are modulated by other neurotransmitters systems, including neuronal histaminergic system. Among the histamine receptors, H3 receptor stands out due to its role in modulation of histamine and other neurotransmitters release. Thus, histaminergic system, through H3 receptors, may have an important role in ethanol addiction development. Aiming to understand these interactions, Conessine, an H3 receptor antagonist, was given to mice subjected to the evaluation of ethanol-induced psychostimulation, ethanol CPP and quantification of norepinephrine, dopamine, serotonin and their metabolites in mesocorticolimbic and nigrostriatal pathways following acute ethanol treatment. Systemic Conessine administration exacerbated ethanol effects on locomotor activity. Despite of Conessine reinforcing effect on CPP, this drug did not alter acquisition of ethanol CPP. Ethanol treatment affects the serotoninergic neurotransmission in the ventral tegmental area, the dopaminergic neurotransmission in the pre-frontal cortex (PFC) and caudate-putamen nucleus (CPu) and the noradrenergic neurotransmission in the CPu. In the PFC, Conessine blocked ethanol effects on dopaminergic and noradrenergic neurotransmission. The blockade of H3 receptors and ethanol seem to interact in the modulation of dopaminergic neurotransmission of nigrostriatal pathway, decreasing dopamine metabolites in substantia nigra. In conclusion, Conessine was able to change psychostimulant effect of ethanol, without altering its reinforcing properties. This exacerbation of ethanol-induced psychostimulation would be related to alterations in dopaminergic neurotransmission in the nigrostriatal pathway.

Holarrhena antidysenterica Extract and Its Steroidal Alkaloid, Conessine, as Resistance-Modifying Agents Against Extensively Drug-Resistant Acinetobacter baumannii.[Pubmed:26745443]

Microb Drug Resist. 2016 Jun;22(4):273-82.

Emergence and spread of antibiotic-resistant Acinetobacter baumannii have become a major public health concern. This study was designed to investigate the efficacy of Holarrhena antidysenterica extract and its major steroidal alkaloid Conessine as resistance-modifying agents (RMAs) on the susceptibility of A. baumannii to novobiocin and rifampicin. A significant synergistic activity of both the extract and Conessine in combination with either novobiocin or rifampicin with fractional inhibitory concentration index Conessine was not observed indicating that both substances did not act as permeabilizers. With regard to efflux pump inhibition, no accumulation in ethidium bromide (EtBr) was noticed suggesting that the AdeABC pump was not involved. In contrast, accumulation in Pyronin Y was significantly increased (p < 0.05) demonstrating that the synergism was due to interference with the AdeIJK pump. Study on frequencies of the spontaneous mutational resistance to the extract in combination with antibiotics demonstrated attenuation in drug-resistant organisms. Thus, H. antidysenterica extract and Conessine as RMAs may offer a combinatory therapy to restore antibiotic susceptibility in the extensively drug-resistant A. baumannii.

Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.[Pubmed:27257813]

PLoS One. 2016 Jun 3;11(6):e0157096.

Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of Conessine are poorly understood. Accordingly, we evaluated the involvement of Conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and Conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with Conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that Conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

Anti-malarial property of steroidal alkaloid conessine isolated from the bark of Holarrhena antidysenterica.[Pubmed:23758861]

Malar J. 2013 Jun 10;12:194.

BACKGROUND: In the face of chronic and emerging resistance of parasites to currently available drugs and constant need for new anti-malarials, natural plant products have been the bastion of anti-malarials for thousands of years. Moreover natural plant products and their derivatives have traditionally been a common source of drugs, and represent more than 30% of the current pharmaceutical market. The present study shows evaluation of anti-malarial effects of compound Conessine isolated from plant Holarrhena antidysenterica frequently used against malaria in the Garhwal region of north-west Himalaya. METHODS: In vitro anti-plasmodial activity of compound was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined compound were determined on L-6 cells of rat skeletal muscle myoblast. The four-day test for anti-malarial activity against a chloroquine-sensitive Plasmodium berghei NK65 strain in BALB/c mice was used for monitoring in vivo activity of compound. In liver and kidney function test, the activity of alkaline phosphatase (ALP) was examined by p-NPP method, bilirubin by Jendrassik and Grof method. The urea percentage was determined by modified Berthelot method and creatinine by alkaline picrate method in serum of mice using ENZOPAK/CHEMPAK reagent kits. RESULTS: Compound Conessine showed in vitro anti-plasmodial activity with its IC(5)(0) value 1.9 mug/ml and 1.3 mug/ml using schizont maturation and pLDH assay respectively. The compound showed cytotoxity IC(5)(0)= 14 mug/ml against L6 cells of rat skeletal muscle myoblast. The isolated compound from plant H. antidysenterica significantly reduced parasitaemia (at 10 mg/kg exhibited 88.95% parasite inhibition) in P. berghei-infected mice. Due to slightly toxic nature (cytotoxicity = 14), biochemical analysis (liver and kidney function test) of the serum from mice after administration of Conessine were also observed. CONCLUSION: The present investigation demonstrates that the compound Conessine exhibited substantial anti-malarial property. The isolated compound could be chemically modified to obtain a more potent chemical entity with improved characteristics against malaria.

The alkaloid conessine and analogues as potent histamine H3 receptor antagonists.[Pubmed:18683917]

J Med Chem. 2008 Sep 11;51(17):5423-30.

The naturally occurring alkaloid, Conessine (6), was discovered to bind to histamine H3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H3 receptors (pKi = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H1, H2, and H4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentrations. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on Conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. One optimized analogue (13c) was examined in detail and was found to be efficacious in animal behavioral model of cognition.

Isolation, characterization and antiplasmodial activity of steroidal alkaloids from Funtumia elastica (Preuss) Stapf.[Pubmed:15863333]

Bioorg Med Chem Lett. 2005 May 16;15(10):2637-40.

Bioassay-guided fractionation of the EtOH extract of the stem bark of Funtumia elastica resulted in the isolation of four steroidal alkaloids, holarrhetine (1), Conessine (2), holarrhesine (3) and isoconessimine (4). Their structures were determined on the basis of 1D- and 2D-NMR techniques and mass spectrometry. Compounds 1-4 exhibited in vitro antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum with IC50 values ranging from 0.97 to 3.39 microM. They showed weak cytotoxicity against a rat cell line L-6 with IC50 values ranging from 5.13 to 36.55 microM.