L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the ba...L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.展开更多
The aversive properties of alcohol can be examined by using ethanol as a conditioning agent in a taste aversion (TA) paradigm. However, there is often variability in how organisms respond to the aversive properties of...The aversive properties of alcohol can be examined by using ethanol as a conditioning agent in a taste aversion (TA) paradigm. However, there is often variability in how organisms respond to the aversive properties of alcohol. Using a selectively bred line of TA-prone (TAP) rats, the present study sought to determine if antagonizing the GABA receptor complex with picrotoxin could block the acquisition of an ethanol-based conditioned aversion to a normally preferred fluid. Fifty TAP rats were randomly divided into 5 groups. In the two experimental groups, rats were pretreated with i.p. injections of low or high doses of the GABA Aantagonist picrotoxin prior to undergoing taste aversion conditioning —wherein consumption of a novel saccharin solution (0.1%) was followed by an i.p. injection of ethanol (1.5 mg/kg). In the primary control group, rats were treated identically, except that isotonic saline was substituted for picrotoxin. In the non-conditioning and pseudo-conditioning control groups, rats did not receive an ethanol-saccharin pairing but did receive a picrotoxin injection. Repeated measures ANOVA revealed that animals in the picrotoxin groups displayed significantly weaker TAs than the primary control group (p 0.05) as measured by post-conditioning, two-bottle saccharin preference scores. Picrotoxin hinders the acquisition of an ethanol-induced TA, thereby supporting the hypothesis that the GABA system plays a central role in ethanol’s motivational effects. Possible mechanisms include 1) picrotoxin attenuates negative effects of ethanol, 2) picrotoxin interferes with the central associative processes that promote TA conditioning or 3) some combination of 1 and 2.展开更多
Gamma-aminobutyric acid(GABA),widely existing in different organisms,is rapidly accumulated in plants in response to environmental stresses.The main biosynthesis and degradation pathways of GABA constitute the GABA sh...Gamma-aminobutyric acid(GABA),widely existing in different organisms,is rapidly accumulated in plants in response to environmental stresses.The main biosynthesis and degradation pathways of GABA constitute the GABA shunt,which is tied to the tricarboxylic acid(TCA)cycle.GABA transaminase(GABA-T)and succinate semialdehyde dehydrogenase(SSADH)are two essential enzymes for the GABA degradation pathway.While there are abundant studies on GABA shunt in higher plants at the physiological and genetic levels,research on its role in microalgae remains limited.This study aimed at exploring the function of GABA-T and SSADH genes in Isochrysis zhanjiangensis,an important diet microalga,under different stresses.We cloned two GABA-T genes,IzGABA-T1 and IzGABA-T2,and one SSADH gene IzSSADH from Isochrysis zhanjiangensis and conducted heterologous expression experiments.The results showed that the overexpression of IzGABA-T1 or IzGABA-T2 enhanced the survival rates of yeast transformants under heat or NaCl stress,while the overexpression of IzSSADH improved yeast tolerance to NaCl stress but had no obvious effect on heat stress.Additionally,the results of quantitative real-time polymerase chain reaction(qPCR)showed that IzGABA-T1 transcription increased in the HT(salinity 25,35℃)and LS(salinity 15,25℃)groups.At 24 h,the IzGABA-T2 transcriptions increased in the HT,LS,and HS(salinity 35,25℃)groups,but their transcription levels decreased in all groups at 48 h.IzSSADH transcription increased in the LS group.These results suggest that IzGABA-T1,IzGABA-T2,and IzSSADH are associated with temperature and salinity stresses and possess a certain preference for different stresses.展开更多
This article summarized the research progress on the antidepressant mechanism of icariin II,mainly elaborating on its mechanism from five aspects:GABAergic nervous system,inflammatory response,oxidative stress,neurotr...This article summarized the research progress on the antidepressant mechanism of icariin II,mainly elaborating on its mechanism from five aspects:GABAergic nervous system,inflammatory response,oxidative stress,neurotrophic factors,and neurotransmitters in the brain.Its clinical application value was further explored to provide a theoretical basis for the development and utilization of icariin II in treating depression.展开更多
文摘L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.
文摘The aversive properties of alcohol can be examined by using ethanol as a conditioning agent in a taste aversion (TA) paradigm. However, there is often variability in how organisms respond to the aversive properties of alcohol. Using a selectively bred line of TA-prone (TAP) rats, the present study sought to determine if antagonizing the GABA receptor complex with picrotoxin could block the acquisition of an ethanol-based conditioned aversion to a normally preferred fluid. Fifty TAP rats were randomly divided into 5 groups. In the two experimental groups, rats were pretreated with i.p. injections of low or high doses of the GABA Aantagonist picrotoxin prior to undergoing taste aversion conditioning —wherein consumption of a novel saccharin solution (0.1%) was followed by an i.p. injection of ethanol (1.5 mg/kg). In the primary control group, rats were treated identically, except that isotonic saline was substituted for picrotoxin. In the non-conditioning and pseudo-conditioning control groups, rats did not receive an ethanol-saccharin pairing but did receive a picrotoxin injection. Repeated measures ANOVA revealed that animals in the picrotoxin groups displayed significantly weaker TAs than the primary control group (p 0.05) as measured by post-conditioning, two-bottle saccharin preference scores. Picrotoxin hinders the acquisition of an ethanol-induced TA, thereby supporting the hypothesis that the GABA system plays a central role in ethanol’s motivational effects. Possible mechanisms include 1) picrotoxin attenuates negative effects of ethanol, 2) picrotoxin interferes with the central associative processes that promote TA conditioning or 3) some combination of 1 and 2.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY22C190001)the Natural Science Foundation of Ningbo Government(No.2021J114)+3 种基金the Ningbo Science and Technology Research Projects,China(No.2019B10006)the Zhejiang Provincial Department of Education Scientific Research Project(No.Y202249030)the Earmarked Fund for CARS-49partly sponsored by K.C.Wong Magna Fund in Ningbo University.
文摘Gamma-aminobutyric acid(GABA),widely existing in different organisms,is rapidly accumulated in plants in response to environmental stresses.The main biosynthesis and degradation pathways of GABA constitute the GABA shunt,which is tied to the tricarboxylic acid(TCA)cycle.GABA transaminase(GABA-T)and succinate semialdehyde dehydrogenase(SSADH)are two essential enzymes for the GABA degradation pathway.While there are abundant studies on GABA shunt in higher plants at the physiological and genetic levels,research on its role in microalgae remains limited.This study aimed at exploring the function of GABA-T and SSADH genes in Isochrysis zhanjiangensis,an important diet microalga,under different stresses.We cloned two GABA-T genes,IzGABA-T1 and IzGABA-T2,and one SSADH gene IzSSADH from Isochrysis zhanjiangensis and conducted heterologous expression experiments.The results showed that the overexpression of IzGABA-T1 or IzGABA-T2 enhanced the survival rates of yeast transformants under heat or NaCl stress,while the overexpression of IzSSADH improved yeast tolerance to NaCl stress but had no obvious effect on heat stress.Additionally,the results of quantitative real-time polymerase chain reaction(qPCR)showed that IzGABA-T1 transcription increased in the HT(salinity 25,35℃)and LS(salinity 15,25℃)groups.At 24 h,the IzGABA-T2 transcriptions increased in the HT,LS,and HS(salinity 35,25℃)groups,but their transcription levels decreased in all groups at 48 h.IzSSADH transcription increased in the LS group.These results suggest that IzGABA-T1,IzGABA-T2,and IzSSADH are associated with temperature and salinity stresses and possess a certain preference for different stresses.
文摘This article summarized the research progress on the antidepressant mechanism of icariin II,mainly elaborating on its mechanism from five aspects:GABAergic nervous system,inflammatory response,oxidative stress,neurotrophic factors,and neurotransmitters in the brain.Its clinical application value was further explored to provide a theoretical basis for the development and utilization of icariin II in treating depression.
