الفهرس 
Acknowledgment
physiological resultsOnly 14 pages are availabe for public view
 |  | from | 220 |  |  |
| | | from | 220 | | |
Abstract
PD is a chronically progressive, age-related, incapacitating movement disorder in humans. Estimates indicate that 4–6 million people have been diagnosed with PD and that ≈2% of the population will suffer from the disease at some time in life. In both idiopathic and genetic cases of PD, oxidative stress is thought to be the common underlying mechanism that leads to cellular dysfunction and demise.
Till now there’s no definite treatment for PD only symptomatic treatment. In this experimental study we used curcumin as the natural herbal antioxidant and a novel indole derivative to antagonize the oxidative stress in PD.
Forty adult male albino rats were used in this study and divided into two main groups (I & II).
group I (Control group) (n 10 rats): were further subdivided equally into two subgroups; group IA: not received vehicle and group IB: received six S.C. injections of the vehicle (DMSO+PEG-300, 1:1 v/v) in a volume of 5 ml/kg every 48h for 11days.
group II: Parkinson’s model group (n 30 rats): received six doses of rotenone (1.5 mg/kg/48 h, S.C.) dissolved in DMSO+PEG-300, 1:1 v/v in a volume of 5 ml/kg to induce experimental Parkinsonism. Animals were subdivided into 3 subgroups, 10 rats each. group (IIA): served as control for Parkinson’s disease group. group (IIB): from the first day of rotenone injection, rats received curcumin (300 mg/kg) orally once per day for 15 days. group (IIC): from the first day of rotenone injection, rats received a novel indole derivative in a dose of 10 mg/kg administered orally once per day for 15 days.
At the end of the experiment, physiological tests were done for the assessment of the locomotor activity. Blood samples were taken for TAC measurements and striatal dopamine levels were measured. Specimens of the midbrain were processed for histological, morphometric and immunohistochemical study of the SNc.
Rotenone treatment induced PD like symptoms which were observed by physiological tests. Apoptotic and rarely secondary necrotic degeneration of SNc dopaminergic neurons detected by histological, morphometric and immunohistochemical examinations. Ultrastructure characteristically revealed Golgi fragmentation in neuronal somata, microtubules disorganization in neuronal processes. Morphometry demonstrated significant decrease in number of TH-positive neurons and significant increase in the number of caspase-3 positive neurons.
This work demonstrated that the effect of oxidative stress and mitochondrial dysfunction of rotenone extended to involve both glial cells and blood vessels. Rotenone Parkinson model, revealed a mild reactive astrocytosis; the astrocytes did not display any glial filaments up regulation, the astrocytes increased in number. The ultrastructure of the astrocytic mitochondria showed inner membrane conformation change to the vesicular form and disruption of the outer one and some mitochondrial contents were released and surrounded by phagophore. The appearance of the new microglial phenotype; the dark microglia was remarkable in rotenone group beside the mild astrocytosis. Vascular vulnerability to rotenone was manifested by endothelial disruption and degeneration, string vessel formation, pericytes degenerations and significant increase in number of blood capillaries. These changes would consequently result in dys¬function in the blood–brain barrier transporter system.
The results demonstrated that curcumin and the novel indole derivative played an important antioxidant activity and neuroprotective effect and consequently reduced the rotenone toxicity. This was approved by physiological tests, analysis of TAC and striatal dopamine levels.
Histologically, Parkinson treated groups revealed that most of SNc neurons and glial cells were normal, and degenerative changes in blood capillaries were rarely observed. Morphometric and immunohistochemical examinations of the Parkinson treated groups exhibited a significant increase in the number of TH positive neurons and a significant decreases in the number of caspase-3 positive neurons, in the number of astrocytes and the number of blood capillaries when compared with group IIA. Insignificant differences of these measures existed between groups IIB & IIC.
Conclusions:
- Rotenone Parkinson’s model induces neuronal death.
- Neuronal death in rotenone Parkinson’s model occurs by apoptosis.
- Rotenone Parkinson’s model induces mild astrocytosis.
- Astrocytes do not participate in the progress of neuronal damage in rotenone Parkinson model.
- Rotenone Parkinson’s model induces early apoptotic signs (mitochondrial disruption) in astrocytes.
- Blood brain barrier dysfunction could contribute to the pathogenesis of PD.
- Curcumin and the novel indole derivative exert a neuroprotective effect in rotenone Parkinson’s model.