phenanthrenes and Encephalitis

Parkinson's disease (PD) is a type of motor system disorder that results from the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) of the midbrain. It is one of the most common neurodegenerative disorders, with an incidence that is second only to Alzheimer's disease (AD). Although replacement of dopamine can temporarily alleviate the symptoms of PD patients, it can not prevent the progression of the disease. Increasing evidence has suggested that neuroinflammation significantly contributes to the progress of PD. Therefore, anti-inflammatory therapy could represent a promising neuroprotective intervention with the potential to delay or prevent onset of the disease. This review summarizes several novel potential agents/candidates that might open new avenues for the treatment of PD. In addition to possessing demonstrated anti-inflammatory activities that operate through different molecular mechanisms, these agents exert neuroprotective effects by enhancing the production of neurotrophic factors or interfering with the apoptosis of neurons.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cytoprotection; Diterpenes; Encephalitis; Epoxy Compounds; Glatiramer Acetate; Humans; Microglia; Minocycline; Neuroprotective Agents; Parkinson Disease; Peptides; Phenanthrenes

Chronic pain and depression frequently coexist in clinical setting, and current clinical treatments for this comorbidity have shown limited efficacy. Triptolide (T10), an active component of Tripterygium wilfordii Hook F., has been demonstrated to exert strong analgesic activities in experimental pain models, but whether it possesses anti-depressive actions remains unknown. Using a depression comorbidity of chronic pain rat model induced by spinal nerve ligation (SNL), we investigated the potency of T10 for the treatment of comorbid depression in comparison with a widely used antidepressant, fluoxetine (FLX). Concomitant neuroinflammation changes were also examined in the hippocampus. The results showed that prophylactic and reversal treatments with T10 dose-dependently (30, 100, 300μg/kg) inhibited the depression-like behaviors (DLB) assessed by the forced swim test, sucrose preference test and body weight measurement. The anti-depressive efficacy of T10 at 300μg/kg was significantly stronger than that of FLX at 18mg/kg. T10 at all three doses exhibited more efficient analgesic effects than FLX at 18mg/kg. The combined application of T10 with FLX markedly augmented the effects of T10 or FLX per se, with the facilitating effects of T10 at 30μg/kg being most prominent. In addition, nerve injury caused the activation of microglia and p38 MAPK, the upregulation of IL-1β and TNF-α as well as the downregulation of IL-10 in the hippocampus at postoperative week (POW) 3. These neuroinflammatory responses were reversed by subchronic treatment with T10. Taken together, these results demonstrate that T10 possesses potent anti-depressive function, which is correlated with its immunoregulation in the hippocampus. The combination of a low dose of T10 with FLX may become a more effective medication strategy for the treatment of comorbid depression and chronic pain.

Topics: Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Chronic Pain; Depression; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Encephalitis; Epoxy Compounds; Fluoxetine; Hippocampus; Hyperalgesia; Inflammation Mediators; Male; Microglia; Phenanthrenes; Rats, Sprague-Dawley

Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson's disease (PD). The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium (MPP+)-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP+.. The rat model of PD was established by intranigral microinjection of MPP+. At baseline and on day 1, 3, 7, 14, 21 following MPP+ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 (microglia marker) in the substantia nigra (SN). The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase (TH) positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry.. Intranigral injection of MPP+ resulted in robust activation of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances.. These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP+-induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP+-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Biomarkers; CD11b Antigen; Cell Count; Cell Survival; Disability Evaluation; Diterpenes; Dopamine; Encephalitis; Epoxy Compounds; Gliosis; Herbicides; Immunosuppression Therapy; Immunosuppressive Agents; Male; Microglia; Neurons; Parkinsonian Disorders; Phenanthrenes; Rats; Rats, Sprague-Dawley; Substantia Nigra; Treatment Outcome; Tyrosine 3-Monooxygenase