phenanthrenes and Parkinsonian-Disorders

To investigate the neuroprotective effects of LLDT-67, a novel derivative of triptolide, in MPTP-induced mouse Parkinson's disease (PD) models and in primary cultured astrocytes, and to elucidate the mechanisms of the action.. In order to induce PD, C57BL/6 mice were injected MPTP (30 mg/kg, ip) daily from d 2 to d 6. MPTP-induced behavioral changes in the mice were examined using pole test, swimming test and open field test. The mice were administered LLDT-67 (1, 2, or 4 mg/kg, po) daily from d 1 to d 11. On d 12, the mice were decapitated and brains were collected for immunohistochemistry study and measuring monoamine levels in the striatum. Primary cultured astrocytes from the cortices of neonatal C57BL/6 mouse pups were prepared for in vitro study.. In MPTP-treated mice, administration of LLDT-67 significantly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and ameliorated the behavioral changes. LLDT-67 (4 mg/kg) significantly increased the expression of NGF in astrocytes in the substantia nigra and striatum of the mice. Furthermore, administration of LLDT-67 caused approximately 2-fold increases in the phosphorylation of TrkA at tyrosine 751, and marked increases in the phosphorylation of AKT at serine 473 as compared with the mice model group. In the cultured astrocytes, LLDT-67 (1 and 10 nmol/L) increased the NGF levels in the culture medium by 179% and 160%, respectively.. The neuroprotective effect of LLDT-67 can be mostly attributed to its ability to enhance NGF synthesis in astrocytes in the midbrain and to rescue dopaminergic neurons indirectly through TrkA activation.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Animals, Newborn; Astrocytes; Cells, Cultured; Corpus Striatum; Disease Models, Animal; Diterpenes; Dopaminergic Neurons; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factor; Neuroprotective Agents; Parkinsonian Disorders; Phenanthrenes; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, trkA; Substantia Nigra; Time Factors; Up-Regulation

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

To study the protective effects of triptolide (Tri) on the lipopolysaccharide (LPS)-mediated degeneration of dopaminergic neurons in substantia nigra.. Forty SD rats were randomly divided into four groups: the sham group, the LPS model group, the Tri group and the normal saline group, 10 in each group. Fourteen days later, the apomorphine-induced rotational behavior, the content of dopamine (DA) and its metabolites in the striatum of the injured side, the number of tyrosine-hydroxylase (TH) positive neurons and activation of microglia in rats were observed.. Injection of LPS in substantia nigra could induce cerebral simulated immunoinflammatory reaction, leading to degeneration of dopaminergic neuron and induce ipsilateral directed rotational behavior of rats, which could be improved by Tri. Moreover, Tri could raise the lowered content of DA and its metabolites as well as the TH positive neurons in striatum, and suppress the activation of microglia significantly (P<0.01).. Tri could protect the dopaminergic neurons from degeneration due to the inflammation mediated by LPS through inhibiting the activation of microglia.

Topics: Animals; Diterpenes; Dopamine; Epoxy Compounds; Female; Inflammation Mediators; Lipopolysaccharides; Neurons; Neuroprotective Agents; Parkinsonian Disorders; Phenanthrenes; Phytotherapy; Random Allocation; Rats; Rats, Sprague-Dawley; Substantia Nigra