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In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

This study examined the effect of dihydroquercetin (DHQ), also knofigurewn as taxifolin, on rotenone‐induced Parkinsonism in rats. Male Wistar rats were administered 1.5 mg/kg rotenone for 10 days and subsequently treated with 0.25–1.0 mg/kg DHQ for 3 days followed by the assessment of parkinsonian symptoms. Brain striatal redox stress and neurochemical dysfunction markers were assessed spectrophotometrically. Histopathological evaluation of the striatum was done by hematoxylin and eosin staining technique. The expression of genes involved in the activation of NF‐κB signaling pathway (IL‐1β, TNF‐α, NF‐κB and IκKB), and the p53 gene in the striatum were determined by RT‐qPCR. DHQ attenuated parkinsonian symptoms as well as striatal redox stress, neurochemical dysfunction, and histological alterations occasioned by rotenone toxicity. Importantly, DHQ significantly suppressed the rotenone‐induced upregulation of IL‐1β, NF‐κB, and IκKB expression (p < 0.05) in the striatum of parkinsonian rats. DHQ demonstrated notable neurotherapeutic potential against rotenone‐induced Parkinsonism in rats by improving parkinsonian symptoms (bradykinesia, catalepsy, postural instability, impaired locomotor behavior, and tremor) and neurochemical dysfunctions via modulation of genes involved in the activation of the canonical pathway of NF‐κB‐mediated inflammation. [ABSTRACT FROM AUTHOR]

In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.

In February 2012 the Rondegat River, in the Cape Floristic Region, was the first river in South Africa where the piscicide rotenone was used to remove an alien invasive fish, smallmouth bassMicropterus dolomieu. In preparation for this treatment, the sensitivity of smallmouth bass to various concentrations of the rotenone formulation CFT Legumine (5% active rotenone) was evaluated a week prior to treatment using standard toxicity tests to determine the minimum effective dose (MED) that would result in 100% mortality after exposure for 4 h. The MED was 0.0125 mg l-1rotenone. Adverse effects, including erratic swimming, loss of equilibrium and death, occurred in a dose-dependent manner with smaller fish responding faster than larger ones. Standard operating procedures for the use of rotenone recommend treatment at a minimum of twice the calculated MED. Given the uncertainty associated with rotenone losses through hydrolysis and photolysis under field conditions, and the possible occurrence of smallmouth bass more tolerant than those tested, a concentration of twice the recommended treatment dose (0.050 mg l-1rotenone) was finally used to treat the Rondegat River for a duration of 6 h. [ABSTRACT FROM PUBLISHER]

The aim of the present studies was to characterise cell death following inhibition of mitochondrial complex I with rotenone in a transformed cell line (RGC-5 cells) and to examine the neuroprotective properties of the flavonoids genistein, epigallocatechin gallate (EGCG), epicatechin (EC) and baicalin. Rotenone-induced cell death of RGC-5 cells results in a generation of reactive oxygen species, a breakdown of DNA, the translocation of membrane phosphatidylserine, an up-regulation of haemoxygenase-1 and is unaffected by necrostatin-1 (inhibitor of necroptosis), z-VAD-fmk (pan caspase inhibitor) or NU1025 (PARP inhibitor) but attenuated with SP600125 (JNK inhibitor). Rotenone-induced toxicity of RGC-5 cells also caused an activation of mitogen-activated kinases indicated by an up-regulation and translocation into mitochondria of p-c-Jun, pJNK and pp38. Exposure of RGC-5 cells to rotenone does not affect apoptosis inducing factor or significantly stimulate caspase-3 activity. EGCG and EC both significantly blunt rotenone toxicity of RGC-5 cells at concentrations of 50 μM while genistein and baicalin were without effect. Significantly, genistein is approximately 20 times less efficacious than EGCG (IC 2.5 μM) and EC (IC 1.5 μM) at inhibiting sodium nitroprusside-induced lipid peroxidation. These studies show that rotenone toxicity of RGC-5 cells is neither necroptosis nor caspase-dependent apoptosis but involves the activation of mitogen-activated kinases and is inhibited by a JNK inhibitor, EGCG and EC. Genistein attenuates lipid peroxidation less efficaciously than EC and EGCG and does not affect rotenone toxicity of RGC-5 cells. [ABSTRACT FROM AUTHOR]

Background: Mutations in LRRK2 are among the most frequent genetic changes identified in Parkinson’s disease (PD), but how LRRK2 contributes to the pathophysiology of PD is not known. Objectives: To investigate how expressing wild-type or G2019S LRRK2 modifies cellular responses to rotenone, a mitochondrial toxin. Methods: We investigated the vulnerability to mitochondrial toxins in Caenorhabditis elegans expressing wild-type or G2019S LRRK2. Results: We observed a powerful role for LRRK2 in mitochondrial biology. Overexpressing LRRK2 strongly protects C. elegans against rotenone toxicity. The G2019S LRRK2 construct also protected LRRK2 against rotenone, but to a lesser degree than wild-type LRRK2. Knockdown of lrk-1 potentiated rotenone toxicity. Conclusions: These data suggest that LRRK1/2 regulate mitochondrial physiology. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]