الفهرس 
Introduction & Aim of the workOnly 14 pages are availabe for public view
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Abstract
The present study was conducted to evaluate the neuroprotective effects of GLP-1R stimulation either directly by using agonist (exenatide) or indirectly by using DPP-4 inhibitor (sitagliptin) in animal model of PD.
The PD was induced in rats by using rotenone (1.5mg/kg/s.c.) dissolved in 1:1 (v/v) DMSO/PEG-400. Rotenone was administered for a total period of seventeen days (received nine subcutaneous injections) on every other day. Behavioral tests and tissue sampling were performed on the last day of the experiment (3rd day after the last rotenone injection).
Before starting experiment, rats were subjected to three day training sessions using pole test in order to train on pole test, and placed in open field box to habituate it. On the fourth day of the training session, all pharmacological treatments were started two weeks before rotenone injection and continued till last rotenone dose.
Rats were randomly divided into seven groups, fourteen rats each. All groups injected with rotenone, except the normal and vehicle-injected group which were received nine subcutaneous injections of DMSO/PEG-400 (1.5mg/kg), as described below.
group I: normal group
group II: (Vehicle-injected group) nine subcutaneous injections of the vehicle (DMSO+PEG-400, 1:1 v/v), 1.5mg/kg/s.c, every other day.
group III: (Rotenone group) will receive nine doses of rotenone (1.5mg/kg/s.c.) every other day to induce experimental Parkinsonism.
group IV: sitagliptin (20mg/kg/once daily, p.o).
group V: sitagliptin (30mg /kg/once daily, p.o).
group VI: Exenatide (0.1ug/kg/twice daily, i.p).
group VII: Exenatide (0.5ug/kg/twice daily, i.p).
On the last day of the experiment (3rd day after the last rotenone injection), rats were evaluated for behavioral tests (open field test and pole test), then scarified. Brains were quickly isolated and washed in ice-cold saline. Six brains from each group were collected in 10% neutral buffered formalin for histopathological and immunohistochemistry evaluations. The remaining brains were immediately frozen at -80 °C for biochemical evaluation of striatal DA level after their homogenization.
The results of the present study could be summarized as follow:
Effect of administration of rotenone
• Administration of rotenone (1.5mg/kg, s.c.) for seventeen days on every other day for a total of nine subcutaneous injections resulted in a significant (P ≤ 0.05) decrease in locomotor activity tested by open field (no of crossed lines and rearing) and increase in pole test time (T-turn and T-total) as compared to normal group.
• Histopathological examination of nigral tissue either by using H&E stain or immunohistopathological analysis of TH (rate limiting enzyme in DA synthesis), which showed a significant (P ≤ 0.05) damage of dopaminergic neurons in this area of the brain after rotenone insultation as compared to normal group.
• Moreover, apoptotic markers (bax, caspase-3) increased significantly
(P ≤ 0.05) versus anti-apoptotic markers (bcl2) which decreased significantly (P ≤ 0.05) as compared to normal group after rotenone insultation in immuno-stained nigral tissue that explained mechanism by which PD progresses.
• Neurochemical evaluation of striatal DA level didn’t decrease significantly as compared to normal group may be revealed to compensatory mechanisms that overcome the expected loss in neurotransmitter DA.
Effect of sitagliptin on rotenone-insulted rats
Sitagliptin (20mg/kg or 30mg/kg, p.o) administration to rats once daily two weeks before rotenone insultation and conducted till last dose of rotenone resulted in:
• Increase the locomotor activity of rats in open field test, and decrease the time spent by animals to turn around or descend a pole in pole test significantly (P ≤ 0.05) as compared to control group.
• Decrease loss in dopaminergic neurons significantly (P ≤ 0.05) as compared to control group which documented either by H&E stain or by TH immunostaning of nigral tissue.
• Decrease apoptotic markers (bax, caspase-3) and increase anti-apoptotic markers (bcl2) significantly (P ≤ 0.05) in nigral tissues as