- The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson's disease. [Journal Article]
- BRBrain Res Bull 2017 Nov 22; 137:132-139
- The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine (DA) determines the function of the nigrostriatal system for motor coordina...
The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine (DA) determines the function of the nigrostriatal system for motor coordination. We previously showed that 4-pyridinylmethyl-9(10H)-anthracenone (XE991), a specific blocker of Kv7/KCNQ channels, enhanced the excitability of nigral DA neurons and resulted in attenuation of haloperidol-induced catalepsy in a Parkinson's disease (PD) rat model. However, whether XE991 exhibits neuroprotective effects towards DA neuron degeneration remains unknown. The aim of this study was to investigate the effects of Kv7/KCNQ channel blocker, XE991, on 6-hydroxydopamine (6-OHDA)-induced nigral DA neuron degeneration and motor dysfunction. Using immunofluorescence staining and western blotting, we showed that intracerebroventricular administration of XE991 prevented the 6-OHDA-induced decrease in tyrosine hydroxylase (TH)-positive neurons and TH protein expression in the SNc. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) also revealed that XE991 partly restored the levels of DA and its metabolites in the striatum. Moreover, XE991 decreased apomorphine (APO)-induced contralateral rotations, enhanced balance and coordination, and attenuated muscle rigidity in 6-OHDA-treated rats. Importantly, all neuroprotective effects by XE991 were abolished by co-application of Kv7/KCNQ channel opener retigabine and XE991. Thus, Kv7/KCNQ channel inhibition by XE991 can exert neuroprotective effects against 6-OHDA-induced degeneration of the nigrostriatal DA system and motor dysfunction.
- Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin. [Journal Article]
- PBPharmacol Biochem Behav 2015; 138:14-9
- Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this st...
Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.
- Dual regulating effect of Ningdong granule on extracellular dopamine content of two kinds of Tourette's syndrome rat models. [Journal Article]
- BTBiosci Trends 2015; 9(4):245-51
- Tourette's syndrome (TS) is an inherited chronic neuropsychiatric disorder characterized by involuntary stereotyped motor and phonic behaviors called tics. Its pathogenesis is still unclear and its t...
Tourette's syndrome (TS) is an inherited chronic neuropsychiatric disorder characterized by involuntary stereotyped motor and phonic behaviors called tics. Its pathogenesis is still unclear and its treatment remains limited. Our previous basic and clinical studies have shown that traditional Chinese medicine (TCM) preparation Ningdong granule (NDG) is effective for the treatment of TS with little side effects. In the current study, two TS rat models (Apomorphine (Apo)- and 3,3'-iminodipropionitrile (IDPN)-induced) were used to explore the dual regulating effects and mechanisms of NDG on extracellular DA concentration. We found that NDG could regulate the extracellular DA concentration dually: it could make a gradual recovery in extracellular DA content from both an up-regulated level in Apo-induced rats and down-regulated level in IDPN-induced rats measured by high-performance liquid chromatography (HPLC). The protein expression of DA transporter (DAT) was measured by Western blot and the result showed that NDG could elevate DAT expression when DA release was up-regulated and could decrease DAT expression when extracellular DA concentration was down-regulated. The main mechanism of the dual regulating effect of NDG on extracellular DA release might be related to DAT protein expression in TS, through which the released DA is re-uptaken into nerve terminals. Taken together, compared with conventional single-target anti-tics drugs such as haloperidol (Hal), NDG with the dual regulating effect would be more significant for TS treatment.
- Dual regulating effects of gastrodin on extracellular dopamine concentration in rats models of Tourette's syndrome. [Journal Article]
- IJInt J Neurosci 2015; 125(10):784-92
- CONCLUSIONS: The dual regulating effects of gastrodin on extracellular DA level have been established, and the related mechanisms would be the dual regulating effects of gastrodin on the expression of DAT, a glycoprotein in the regulation of the extracellular DA concentration.
- Antipsychotic property of solvent-partitioned fractions of Lonchocarpus cyanescens leaf extract in mice. [Journal Article]
- JBJ Basic Clin Physiol Pharmacol 2014 May 1; 25(2):235-40
- CONCLUSIONS: These findings suggest that EAF contains the major active constituent(s) mediating the antipsychotic property of LC and further support its use for the management of psychosis in traditional medicine.
- Inhibition of 5α-reductase attenuates behavioral effects of D1-, but not D2-like receptor agonists in C57BL/6 mice. [Journal Article]
- PPsychoneuroendocrinology 2013; 38(4):542-51
- Converging lines of evidence point to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly und...
Converging lines of evidence point to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of steroid 5α-reductase (5αR), the key rate-limiting enzyme in neurosteroidogenesis, attenuates the behavioral effects of non-selective DA receptor agonists in rats, including stereotyped responses and sensorimotor gating deficits, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. Since previous findings suggested that the role of DA D(1)- and D(2)-like receptor families in behavioral regulation may exhibit broad interspecies and interstrain variations, we assessed the impact of 5αR blockade on the behavioral effects of DAergic agonists in C57BL/6 mice. The prototypical 5αR inhibitor finasteride (FIN; 25-50 mg/kg, intraperitoneally, IP) dose-dependently countered the PPI deficits and the enhancement of rearing responses induced by the full D(1)-like receptor agonist SKF-82958 (0.3 mg/kg, IP); however, FIN did not significantly affect the hyperlocomotive and startle-attenuating effects of SKF-82958. Whereas the D(2)-like receptor agonist quinpirole (QUIN; 0.5 mg/kg, IP) did not induce significant changes in PPI, the combination of this agent and FIN surprisingly produced marked gating and startle deficits. In contrast with previous data on rats, FIN did not affect the reductions of startle reflex and PPI produced by the non-selective DAergic agonist apomorphine (APO; 0.5 mg/kg, IP). These findings collectively indicate that, in C57BL/6 mice, 5αR differentially modulates the effects of D(1)- and D(2)-like receptor agonists in behavioral regulation.
- Effects of ningdong granule on DA, DRD2, and HVA in a rat model of Tourette's syndrome. [Journal Article]
- JTJ Tradit Chin Med 2012; 32(2):283-8
- CONCLUSIONS: Results demonstrated that Ning-dong granule effectively inhibited stereotype actions and Tourette's syndrome symptoms by promoting dopamine metabolism, reducing dopamine levels in the striatum, increasing homovanillic acid content in sera, and reducing mRNA expression of DRD2 in the striatum.
- Protective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models. [Journal Article]
- PRPharmacol Rep 2012; 64(1):191-204
- Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have...
Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.
- Effects of Ningdong granule on the dopamine system of Tourette's syndrome rat models. [Journal Article]
- JEJ Ethnopharmacol 2009 Jul 30; 124(3):488-92
- CONCLUSIONS: NDG could effectively inhibit the stereotyped behaviors in TS rats, and the mechanisms may be related to the suppression of DA system by increasing the content of HVA in sera, decrease the content of DA and repressing the expression of DRD2 mRNA in striatum.
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- Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine. [Journal Article]
- PPsychopharmacology (Berl) 2009; 203(4):723-35
- CONCLUSIONS: Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.