lignans and Nerve-Degeneration

Two new lignans, 3,4-(10-methoxy-phenylallyl)-9″-((10'-isopropanol-3',4'-furan)-phenylacetyl)-8″-dioxane-7″-O-

Topics: Cell Death; Cell Line; Flowers; Humans; Lignans; Magnetic Resonance Spectroscopy; Magnolia; Molecular Structure; Nerve Degeneration; Neuroprotective Agents; Oxidopamine; Plant Extracts

Parkinson's disease (PD) is a profound neurodegenerative disorder with gradual loss of dopamine nigrostriatal neurons linked to serious behavioral symptoms. While the current treatment strategies present limitations on halting the progression of PD, this study aimed to investigate the therapeutic potential of honokiol, as a partial peroxisome proliferator-activated receptor-gamma (PPARγ) mimic, on the proceeding behavioral and biochemical alterations in hemiparkinsonian mice. Results showed that unilateral striatal 6-hydroxydopamine (6-OHDA)-lesioned mice exhibited motor impairment, reflecting the contralateral rotation induced by apomorphine at 1-3 weeks post-lesion. Subchronic honokiol administration for 1-2 weeks, beginning 7 days after 6-OHDA-lesion, dose-dependently ameliorated motor dysfunction in hemiparkinsonian mice. Recovery of motor function was correlated with reversal of nigrostriatal dopaminergic neuronal loss, accompanied by higher tyrosine hydroxylase (TH) density, dopamine transporter (DAT) expression and vesicular monoamine transporter-2 (VMAT2) levels. Furthermore, honokiol attenuated oxidative stress and reactive astrocyte induction via decreasing NADPH-oxidase and glial fibrillary acidic protein (GFAP) expressions in 6-OHDA-lesioned striatum. The reversal effects of honokiol on behavioral impairment and striatal PPARγ expression were impeded by PPARγ antagonist GW9662. Notably, subchronic honokiol treatment extended the lifespan of these hemiparkinsonian mice. The present findings demonstrate the therapeutic activities of honokiol in ameliorating motor impairment and progressive dopaminergic damage that could be associated with regulating PPARγ signaling. Therefore, honokiol may potentially exert as a novel therapeutic candidate through PPARγ activation for management of motor symptoms and progressive neurodegeneration in PD.

Topics: Animals; Biphenyl Compounds; Gliosis; Lignans; Longevity; Male; Mice; Motor Activity; NADPH Oxidases; Neostriatum; Nerve Degeneration; Oxidation-Reduction; Oxidopamine; Parkinson Disease; PPAR gamma

Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN)-γ and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 μM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-γ/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-γ/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(ω)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Overall, these results indicate that macelignan, a compound with PPARγ agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner.

Topics: Animals; Animals, Newborn; Arginase; Dopaminergic Neurons; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Inflammation; Lignans; Mesencephalon; Microglia; Nerve Degeneration; Neuroprotective Agents; Organ Culture Techniques; Rats; Rats, Wistar

Magnolol has neurotrophic effects in primary cultured rat cortical neurons, which are expressed as the promotion of neurite outgrowth and neuronal survival. In this study, we investigated the protective effect of magnolol against age-related neuronal loss in the hippocampus using senescence-accelerated mouse (SAMP1). Magnolol (5, 10 mg/kg) was orally administered once a day for 14 d to 2- or 4-month-old mice, and evaluation was carried out when the mice were 4 or 6 months old. The density of neurofibrils decreased with aging in the stratum radiatum of the CA1 region in the hippocampus of SAMP1, not SAMR1. Treatment with magnolol significantly prevented the decrease of neurofibrils in the CA1, when it was administered in 2-month-olds. However, administration at 4 months of age did not result in a preventive effect. These findings suggest that the administration of magnolol before the initiation of neuronal loss may result in a protective effect in the hippocampus.

Topics: Aging; Animals; Biphenyl Compounds; Cell Count; Hippocampus; Lignans; Mice; Mice, Inbred Strains; Nerve Degeneration; Neurites; Neurofibrils; Tissue Embedding

The effects of (-)clausenamide (clau) on spatial cognitive functions and hippocampal long-term potentiation (LTP) after transient focal cerebral ischemia in rats were investigated. Four weeks after middle cerebral artery occlusion, Morris water maze tasks demonstrated that 2 h of transient forebrain ischemia resulted in a significant decrease in spatial discrimination performance. The escape latency at 4 and 5 days of acquisition trial was lower in the ischemic rats than in sham-operated rats (33.8+/-6.7 sec and 26.8+/-5 sec versus 12.2+/-4.0 sec and 10.4+/-3.6 sec), chronic treatment with clau (10 mg kg(-1) p.o. once daily) significantly improved the impairment (12.4+/-4.1 sec and 15.2+/-3.1 sec). After Morris water maze, the changes in population spike (PS) amplitude were recorded as an index of LTP in the perforant path-dentate gyrus synapses. There was no difference in PS amplitude between the sham-operated and vehicle-treated animals, whereas the fractional increase of PS 20-50 min after tetanus was significantly larger in clau-treated group. Histopathological analysis revealed that clau could protect against neuron loss in the regions of cortex and striatum. In conclusion, these data indicate a beneficial effect of clau for synaptic plasticity and cognitive function impaired by transient focal cerebral ischemia.

Topics: Action Potentials; Animals; Brain; Brain Ischemia; Cognition Disorders; Drugs, Chinese Herbal; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Lactams; Lignans; Male; Maze Learning; Nerve Degeneration; Neurons; Rats; Rats, Wistar; Recovery of Function; Reperfusion Injury; Treatment Outcome

We previously reported that arctigenin, a lignan isolated from the bark of Torreya nucifera, showed significant neuroprotective activity against glutamate-induced toxicity in primary cultured rat cortical cells. In this study, the mode of action of arctigenin was investigated using primary cultures of rat cortical cells as an in vitro system. Arctigenin significantly attenuated glutamate-induced neurotoxicity when added prior to or after an excitotoxic glutamate challenge. The lignan protected cultured neuronal cells more selectively from neurotoxicity induced by kainic acid than by N-methyl-D-aspartate. The binding of [(3)H]-kainate to its receptors was significantly inhibited by arctigenin in a competitive manner. Furthermore, arctigenin directly scavenged free radicals generated by excess glutamate and successfully reduced the level of cellular peroxide in cultured neurons. These results suggest that arctigenin exerted significant neuroprotective effects on glutamate-injured primary cultures of rat cortical cells by directly binding to kainic acid receptors and partly scavenging of free radicals.

Topics: Animals; Cells, Cultured; Cerebral Cortex; Free Radical Scavengers; Furans; Glutamic Acid; Kainic Acid; Lignans; N-Methylaspartate; Nerve Degeneration; Neurons; Neuroprotective Agents; Peroxides; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid