phenanthrenes and Nerve-Degeneration

Although the exact cause of Alzheimer's disease (AD) remains elusive, mounting evidence continues to support the involvement of neuroinflammation in the development of AD. Triptolide isolated from the herb Tripterygium wilfordii Hook F has anti-inflammatory and immunosuppressive activities. In this study, we observed the effects of triptolide on dendritic spines of hippocampal neurons in model rats with AD. Thirty male SD rats were randomly divided into control group, AD model group and triptolide-treated group. The AD model group was made with bilateral microinjection of aggregated beta-amyloid protein (Aβ)1-40 into hippocampus in rats and the control group rats were injected with normal saline in the same way. The triptolide-treated group rats were administered triptolide intraperitoneally for 30 days after microinjection of aggregated Aβ1-40 into hippocampus. Dendritic morphology of hippocampal neurons in each group was analyzed using Golgi staining and ImageJ software. Our data showed that the total number of intersection points of dendrites and spine density in hippocampal neurons in the AD model group were decreased as compared with the control group. However, the total number of intersection points of dendrites and spine density in hippocampal neurons in the triptolide-treated group were increased as compared with the AD model group. Our results indicate that triptolide can alleviate the degeneration of dendritic spines in hippocampal neurons in model rats with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dendritic Spines; Disease Models, Animal; Diterpenes; Epoxy Compounds; Hippocampus; Immunosuppressive Agents; Male; Nerve Degeneration; Peptide Fragments; Phenanthrenes; Rats; Rats, Sprague-Dawley

Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1). Previously, we showed that Nec-1 protects against glutamate-induced oxytosis by inhibiting the translocation of cellular apoptosis-inducing factor (AIF), a downstream target of PARP-1 activation. In this study, Nec-1 reduced PARP activity but had no effect on the expression of PARP-1 in cells treated with glutamate. Nec-1 also did not protect against cell death mediated by the PARP activator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), although PJ34 did protect against MNNG-mediated cell death. These findings suggest that Nec-1 is not a direct PARP inhibitor and that its signaling target is located upstream of PARP.

Topics: Animals; Apoptosis; Apoptosis Inducing Factor; Cell Line, Transformed; Enzyme Inhibitors; Glutamic Acid; Imidazoles; Indoles; Methylnitronitrosoguanidine; Mice; Necrosis; Nerve Degeneration; Neurotoxins; Oxidative Stress; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Tanshinone IIB (TSB) is a major active constituent of the root of Salvia miltiorrhiza (Danshen) used in the treatment of acute stroke. Danshen extracts and TSB have shown marked neuron-protective effects in mouse studies but there is a lack of clinical evidence for the neuron-protective effects of Danshen and its active ingredients. This study investigated the neuron-protective effects of TSB in experimentally stroked rats. TSB at 5 and 25 mg/kg by intraperitoneal injection significantly reduced the focal infarct volume, cerebral histological damage and apoptosis in rats subjected to middle cerebral artery occlusion (MCAO) compared to MCAO rats receiving vehicle. This study demonstrated that TSB was effective in reducing stroke-induced brain damage and may represent a novel drug candidate for further development. Further mechanistic studies are needed for the neuron-protective activity of TSB.

Topics: Abietanes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Brain; Brain Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Infarction, Middle Cerebral Artery; Injections, Intraperitoneal; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Phenanthrenes; Plant Extracts; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Stroke; Treatment Outcome

Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. Tripchlorolide (TW397), a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, has been shown to protect dopaminergic neurons against, and restore their function after, the neurotoxicity induced by 1-methyl-4-phenylpyridinium ions in vitro. This study was designed to investigate the effect of TW397 in vivo in the PD model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned C57BL/6 mice. In the animals that received vehicle-only (i.e., no TW397) treatment with MPTP i.p. injection, the survival ratios of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta and TH-IR fibres in the striatum were only 59 and 13%, respectively, compared with the normal controls. Intriguingly, in conjunction with MPTP, treatment with TW397, 1 microg/kg for 16 days, once per day, dramatically improved the survival rate of the TH-IR neurons and TH-IR fibres to 80 and 43% of the control. The treatment with TW397 also significantly improved the level of dopamine in the substantia nigra and striatum to 157 and 191%, respectively, of the MPTP- plus vehicle-treated group. In addition, in MPTP-treated animals the rota-rod performances of those treated with 0.5 or 1 microg/kg TW397 were significantly improved, by approximately 2- and 3-fold, respectively, relative to vehicle-treated animals. The neuroprotective effect of TW397 was coincident with an attenuated astroglial response within the striatum. These data demonstrate a neuroprotective action of TW397 in vivo against MPTP toxicity, with important implications for the treatment of PD.

Topics: Animals; Cell Death; Chromatography, High Pressure Liquid; Diterpenes; Dopamine; Immunohistochemistry; Locomotion; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neostriatum; Nerve Degeneration; Nerve Fibers; Neuroprotective Agents; Phenanthrenes; Postural Balance; Serotonin; Substantia Nigra; Tyrosine 3-Monooxygenase

Traumatic brain injury produces peroxynitrite, a powerful oxidant which triggers DNA strand breaks, leading to the activation of poly(ADP-ribose)polymerase-1 (PARP-1). We previously demonstrated that 3-aminobenzamide, a PARP inhibitor, is neuroprotective in a model of traumatic brain injury induced by fluid percussion in rat, suggesting that PARP-1 could be a therapeutic target. In order to confirm this hypothesis, we investigated the effects of PJ34 and INO-1001, two PARP inhibitors from structural classes other than benzamide, on the post-traumatic consequences. Pre- and post-treatments with PJ34 (30 mg/kg/day) and INO-1001 (10 mg/kg/day) decrease the neurological deficit at 3 days post-injury and this deficit is still reduced at 7 days. These neurological recovery-promoting effects are associated with the inhibition of PARP-1 activation caused by trauma, as demonstrated by abolishment of immunostaining of poly(ADP-ribose). Thus, the present work strengthens strongly the concept that PARP-1 inhibition may be a suitable approach for the treatment of brain trauma.

Topics: Animals; Brain; Brain Injuries; Collagen Type XI; Disease Models, Animal; Enzyme Inhibitors; Immunohistochemistry; Indoles; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Recovery of Function; Solubility; Treatment Outcome