|Year : 2012 | Volume
| Issue : 6 | Page : 774-779
Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats
Sawsan A Zaitone1, Dina M Abo-Elmatty2, Shimaa M Elshazly3
1 Department of Pharmacology and Toxicology, Suez Canal University, Ismailia, Egypt
2 Department of Biochemistry, Suez Canal University, Ismailia, Egypt
3 Department of Pharmacology and Toxicology, Zagazig University, Zagazig, Egypt
|Date of Submission||26-Nov-2011|
|Date of Decision||16-Jul-2012|
|Date of Acceptance||31-Aug-2012|
|Date of Web Publication||8-Nov-2012|
Dina M Abo-Elmatty
Department of Biochemistry, Suez Canal University, Ismailia
Source of Support: None, Conflict of Interest: None
Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats.
Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done.
Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P < 0.05).
Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease.
Keywords: Dopamine, Parkinson′s disease, piracetam, rotenone, vinpocetine
|How to cite this article:|
Zaitone SA, Abo-Elmatty DM, Elshazly SM. Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats. Indian J Pharmacol 2012;44:774-9
| » Introduction|| |
Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease that is characterized by irreversible loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Motor features of PD include bradykinesia, rigidity, resting tremor, and abnormalities of balance, posture, and gait.  There is strong evidence that inflammation in the brain, mediated by the activation of microglia, might be involved in the pathogenesis of PD. Under normal conditions, microglial cells, the resident macrophages in the brain, are in a resting state and serve the role of immune surveillance. When subjected to abnormal stimulation, such as neurotoxins or traumatic brain injury, microglia become activated and undergo significant morphological changes. 
The activated microglia secrete a panel of pro-inflammatory cytokines and prostaglandins, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interferon-γ (IFN-γ) and prostaglandin E 2 . Once activated, these cytokine receptors trigger intracellular death-related signaling pathways and lead to the production of inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2) and the activation of NADPH oxidase. This leads to increased inflammation and causes feedback production of cytokines. In addition, microglia cells divide rapidly and produce many potentially noxious compounds, including reactive oxygen species (ROS) and reactive nitrogen species (RNS).  Accumulation of these pro-inflammatory and cytotoxic factors is directly deleterious to neurons and subsequently induces further activation of microglia, finally leading to progressive degeneration of Dopaminergic neurons. , Current drug therapies for human PD with levodopa or various dopamine receptor agonists offer symptomatic relief and appear to have little effect on the neurodegenerative process. 
Although piracetam (PIR) and vinpocetine (VIN) belong to distinct chemical classes, they share the name 'nootropic', the term introduced by Giurgea,  to indicate this category of drugs that enhance memory, facilitate learning and protect memory processes against conditions which tend to disrupt them. Several cognition enhancers are thought to work, at least in part, by protecting the brain from damage, e.g., due to oxidation, free radical damage or neurotoxicity. PIR, the prototype of the so-called 'nootropic' drugs,  is used to treat cognitive impairment in aging, brain injury as well as dementia. PIR is also used in the treatment of cerebral stroke, dementia or cognitive impairment in the elderly. The drug reverses hippocampal membrane alterations in Alzheimer's disease.  PIR possesses a wide variety of neuronal protective actions. In addition, it has been claimed that PIR and other nootropic drugs are capable of reversing certain types of amnesia, to protect against barbiturate-induced neuronal toxicity, and they seem effective, at the clinical level, in mild or moderate dementia. 
VIN (ethyl apovincaminate), widely used as a neuroprotective agent, improves blood circulation, oxygen uptake and glucose utilization by the brain. VIN has been used in brain disorders and treatment of the signs of aging. In addition, VIN is an effective scavenger of hydroxyl radicals and inhibits lipid peroxidation. It can help improve cognitive function and short-term memory in both animals and humans. 
The present study was designed to test the role of the nootropic agents, PIR and VIN in neuroprotection and improving the motor deficits in a rat model of PD. Histopathological examination was also performed to evaluate neuroprotective effect of the nootropic drugs.
| » Materials and Methods|| |
Rotenone (Sigma-Aldrich, MO, USA) was dissolved in 1:1 (v/v) dimethylsulfoxide (DMSO, Sigma-Aldrich, MO, USA) and polyethylene glycol (PEG-300; Sigma-Aldrich, MO, US). PIR powder (Sigma Pharmaceutical Company, Quesna, Egypt) was dissolved in saline. VIN powder was donated by Medical Union Pharmaceuticals (Ismailia, Egypt). It was dissolved in acidic saline (pH = 5.5).
Sixty male Albino rats, obtained from The Egyptian Company for Production of Vaccines (Cairo, Egypt), were used in the present study. The initial body weight of the animals was 200-260 g. The rats were housed in clean stainless steel cages with free access to food and water and controlled laboratory conditions of reversed light-dark cycle and temperature 25 ± 3°C. All experimental protocols were approved by the Institutional Animal Care and Use Committee of Suez Canal University.
The rats were randomly divided into six groups of ten rats each. Group I (vehicle-injected group) received six subcutaneous injections of the vehicle (DMSO+PEG-300, 1:1 v/v) every 48 h. Group II (rotenone group) received six doses of rotenone (1.5 mg/kg/48 h, s.c.) in a volume of 5 ml/kg to induce experimental Parkinsonism More Details.  The daily pharmacological treatment of the other four groups in addition to rotenone was as follows: Group III: PIR (100 mg/kg/day, p.o.); Group IV: PIR (200 mg/kg/day, p.o.);  Group V: VIN (3 mg/kg/day, p.o.); Group VI: VIN (6 mg/kg/day, p.o.).  The pharmacological treatment was administered daily using a gastric tube starting from the first day of rotenone injection and continued until the end of the experiment (day 11).
Motor function of the rats was tested using the open-field test and pole test one day after the last injection of rotenone.
The open-field arena, with the measurements 113×113×44 cm, was made of fumy glass. The floor was painted with white lines that formed a 5×5 cm pattern.  The rats were introduced individually to the open-field arena and observed for ten minutes. The ambulation (the number of squares crossed) and mobility duration (time of paw movement), were scored as described by Conceicao and Frussa-Filho. 
The pole test has been used previously to assess basal ganglia-related movement disorders in rodents.  The rats were placed head-up on top of a vertical wooden pole 50 cm long (1 cm in diameter). The base of the pole was placed in the home cage. When placed on the pole, animals orient themselves downward and descend the length of the pole back into their home cage. The rats received 2 days of training that consisted of 5 trials for each session. On the test day, the animals received 5 trials, and time to orient downward (t-turn) and total time to descend (t-total) were measured. The mean of the 5 trials was used and compared.
Biochemical Analyses of the Brain Tissue Homogenate
After performing the behavioral tests, animals were deeply anesthetized with ether, their brains were quickly removed and washed with ice-cold saline. One hemisphere from each brain was perfused with 10% paraformaldehyde solution and serial coronal sections were cut through the SNpc and were prepared for staining with hematoxylin and eosin (H and E). After staining, the sections were examined using a bright-field microscope.
The striata of the second hemisphere of each brain were isolated, weighed, and used either for extraction of dopamine or for homogenization using a teflon homogenizer (Glas Col homogenizer system, Vernon hills, USA). Homogenization was carried out as 10% (w/v) either in acidified n-butanol (supernatant A) or phosphate-buffered saline (pH = 7.4) (supernatant B). The homogenate was sonicated and centrifuged at 2000×g for 10 min. The supernatants were kept at - 80°C until the analysis of dopamine (supernatant A) and MDA, GSH and TNF-α (supernatant B) were done.
Determination of Dopamine
The supernatant A was subjected to spectroflourometric assay of dopamine following the principle of Ciarlone and Juras. 
Determination of Malondialdehyde
Tissue MDA level was assessed according to the spectrophotometric method of Ohkawa et al.  based on the reaction with thiobarbituric acid using 1, 1, 3, 3-tetramethoxypropane as standard. The color intensity was measured using a UV-visible spectrophotometer (UV-1601PC, Shimadzu, Japan).
Determination of Reduced Glutathione
Concentration of total glutathione (GSH and GSSG) and oxidized glutathione (GSSG) were measured spectrophotometrically using commercial kits according to the instructions of the manufacturer.  Total GSH content was expressed in μM per g protein.
Determination of Tumor Necrosis Factor-α
TNF-α was determined using an ELISA reader (Europe S.A. Belgium), according to Mizutani et al.,  using Biosource International Kits (Camarillo, California, USA).
Neuronal Cells Quantification and Image Analysis
Neuronal cells were quantified stereologically on three regularly spaced sections covering the entire surface of the SNpc as described previously by Hoglinger et al.  Each section was viewed at a low power (×10 magnification) whereas; the cell numbers were counted at high power (×40 magnification). The neurons with clearly visualized nuclei were counted. Neurons were differentiated from other non-neuronal cells by the clearly defined nucleus, cytoplasm and a prominent nucleolus.  After determination of the cell number in each slide, the percentage increase in the cell number relative to rotenone group was calculated and compared.
Values are expressed as mean ± SEM and statistically analyzed using SPSS program, version 17 (SPSS Inc., Chicago, IL, USA). For all analyses, one-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparisons test were applied. P < 0 0.05 was considered statistically significant.
| » Results|| |
In the present study, repeated systemic administration of rotenone to rats (1.5 mg/kg/48 h/6 doses, s.c.) produced motor impairment, histopathological changes and biochemical deficits.
Assessment of Motor Function
It was observed that injection of vehicle in group I did not cause deterioration of the motor performance in the rats in the open field test whereas, rotenone group showed a significant decrease in locomotion, a lower rearing frequency and a shorter mobility duration [Figure 1]. PIR (group IV, 200 mg/kg/day, p.o.) and VIN (group V and VI, 3 or 6 mg/kg/day, p.o.) significantly enhanced the motor activity of the rats in the open field test as compared to rotenone group ( P < 0 0.05).
|Figure 1: Ambulation (a) and mobility duration (b) in the open field test in experimental groups. Results are expressed as mean ± SEM and analyzed using ANOVA followed by Bonferroni's post-hoc test. * P < 0.05 as compared to the vehicle group, # P < 0.05 as compared to rotenone group, ¥ P < 0.05 as compared to PIR (100 mg/kg) group, † P < 0.05 as compared to PIR (200 mg/kg) group. PIR : p0 iracetam, VIN : Vinpocetine|
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Treatment with the high dose of PIR (200 mg/kg) increased the ambulation as compared to rotenone group. Further, treatment with both doses of VIN improved the ambulation and the mobility duration as compared to rotenone group. The low dose of VIN (3 mg/kg) significantly increased the ambulation in comparison to the low dose of PIR. The high dose of VIN (6 mg/kg) significantly improved the ambulation and increased the mobility duration in comparison to both the doses of PIR.
Rotenone-treated rats (group II) showed higher t-turn and t-total compared to vehicle-treated rats (group I). Treatment with PIR (100 or 200 mg/kg) as well as VIN (3 or 6 mg/kg) ameliorated both of the measurements (t-turn and t-total) in the pole test as compared to rotenone group. VIN (6 mg/kg) group showed significantly lowered t-turn and t-total compared to PIR (100 and 200 mg/kg) groups [P < 0 0.05, [Figure 2]a and b].
|Figure 2: Time to orient downward (t-turn) (a) and total time to descend (t-total) (b) in the pole test in experimental groups. Results are expressed as mean ± SEM and analyzed using ANOVA followed by Bonferroni's post-hoc test. *P < 0.05 as compared to the vehicle group, # P < 0.05 as compared to rotenone group, ¥ P < 0.05 as compared to PIR (100 mg/kg) group, † P < 0.05 as compared to PIR (200 mg/kg) group. PIR : Piracetam, VIN : Vinpocetine|
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Biochemical analysis of stress biomarkers in the tissue homogenate of rotenone group demonstrated significant changes as compared to vehicle-injected group
Striatal dopamine content
Rotenone group (1.5 mg/kg/48 h/6 doses, s.c.) showed a significant decrease in dopamine levels compared to vehicle group. Treatment with PIR (200 mg/kg) and VIN (3 or 6 mg/kg) significantly improved the striatal dopamine level as compared to rotenone group [Figure 3].
|Figure 3: Striatal dopamine level in the experimental groups. Results are expressed as mean ± SEM and analyzed using ANOVA followed by Bonferroni's post-hoc test. * P < 0.05 as compared to the vehicle group, # P < 0.05 as compared to rotenone group, ¥ P < 0.05 as compared to PIR (100 mg/kg) group, † P < 0.05 as compared to PIR (200 mg/kg) group. PIR : Piracetam, VIN : Vinpocetine|
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[Table 1] Illustrates that rotenone injection induced approximately five-fold higher concentration of tissue MDA as compared to vehicle-injected group. VIN group showed significantly reduced tissue MDA level as compared to rotenone group. PIR groups did not show similar reduction.
|Table 1: Levels of striatal malondialdehyde, glutathione, and tumor necrosis factor-α in the experimental groups|
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Injection of rotenone in rats induced a significant decrease in the tissue GSH content as compared to the vehicle group (P <0 0.05). Treatment with VIN showed a significant increase in brain GSH in comparison with rotenone group (P < 0 0.05) which was not observed in groups treated with PIR [Table 1].
Tumor Necrosis factor-α
In the present study, striatal TNF-α level was increased in the brains of rotenone group as compared to vehicle group. Treatment with PIR (100 and 200 mg/kg) significantly decreased TNF-α level as compared to rotenone group. VIN had no significant effect on striatal TNF-α level [Table 1].
Histological assessment demonstrated that vehicle-injected rats showed normal SNpc neurons with obvious nuclei. However, rotenone-treated rats showed marked degeneration; neurons appeared with low number/field and with indistinct neuronal boundaries [Figure 4]a. The percent increase in number of dopaminergic neurons per eye field was 244% in the vehicle group compared to 100% in rotenone group. PIR (100 or 200 mg/kg) and VIN (100 or 200 mg/kg) groups showed improved histopathological picture for the SNpc and greater increase in dopaminergic neurons per eye field compared to rotenone group [Figure 4]b.
|Figure 4: (a) Histological changes in the brain of the experimental groups. Vehicle-treated rat shows a number of intact SNpc neurons with visible nuclei. Nigral neurons in rotenone-treated rats (1.5 mg/kg/48 h/6 doses, s.c.) show indistinct neuronal boundaries and invisible nuclei. Treatment with piracetam or vinpocetine significantly increased the number of SNpc neurons (H and E, ´ 240). (b) Percentage increase in the number of dopaminergic neurons in the SNpc in the experimental groups. Results are expressed as mean ± SEM. * P < 0.05 as compared to the vehicle group, # P < 0.05 as compared to rotenone group, ¥ P < 0.05 as compared to PIR (100 mg/kg) group, † P < 0.05 as compared to PIR (200 mg/kg) group. PIR : Piiracetam, VIN : Vinpocetine|
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| » Discussion|| |
Rotenone, a highly selective complex I inhibitor, is known to reproduce the neurochemical, neuropathological, and behavioral features of PD in rats like reduced mobility, flexed posture, and in some cases rigidity, and even catalepsy.  In the present study, rotenone injection in rats impaired motor function and motor coordination. Both the doses of PIR (100 or 200 mg/ kg) enhanced the motor performance in the pole test, decreased striatal TNF-α level and showed greater percentage increase in the dopaminergic neurons in the SNpc in comparison to rotenone group. However, only the high dose of PIR (200 mg/kg) improved the ambulation frequency in the open field test and increased the striatal dopamine level. Treatment with VIN (3 or 6 mg/kg) improved the motor performance of rats in the open field test as well as the pole test. In agreement with the present results, VIN has been shown to improve speed of memory learning and recall in both cognitively healthy subjects and compromised subjects.  Its primary actions are to enhance cerebral vascular blood flow, brain energy metabolism and increase the neuronal uptake of glucose and oxygen. 
It has long been shown that dopamine depletion in the striatum produces profound deficits in reaction time (RT) in rats that may be related to the akinesia and attention dysfunction commonly seen in Parkinsonism.  The current results observed that neuro-pathological changes in the SNpc regions of rotenone-treated rats was accompanied by 59% decrease in striatal dopamine level which is consistent with observations in other studies.  High dose of PIR and both the doses of VIN significantly reversed the decrease seen with rotenone.
In the present study, rotenone-treated rats showed marked increase in striatal MDA concentration, i.e., marker of lipid peroxidation. A recent study showed that elevated oxidative stress may play a role in dopaminergic neuronal loss in SNpc and pathogenesis of PD. In addition, rotenone group demonstrated depletion of striatal GSH concentration and low density of GSH positive cells surrounding the dopaminergic neurons, which along with glutathione peroxidase (G-Px) form the primary defense system of dopaminergic neurons against ROS.  Mitochondrial stabilization and protection might explain many of the beneficial effects of PIR in elderly patients.  PIR was reported to reduce antioxidant enzyme activities only in aged mouse brain, which are elevated as an adaptive response to the increased oxidative stress; hence demonstrating an improvement in mitochondrial dysfunction.  However, in the present study, PIR (100 or 200 mg/kg) did not modify MDA or GSH levels compared to rotenone group. VIN also increased the striatal dopamine and GSH levels whereas it decreased striatal MDA level with subsequent increase in percentage dopaminergic neurons in the SNpc per eye field. VIN is a broad-spectrum antioxidant and neuroprotective agent, especially against calcium overload and neurotoxicity, including the hippocampal/CA1 pyramidal and N-methyl-D-aspartate receptor cells.  It was found that VIN decreased oxidative stress and inhibited ROS formation up to 83% in brain synaptosomes. In addition, VIN demonstrated the ability to attenuate the oxidative stress and metabolic dysfunction induced by amyloid-beta peptides in PC12 cells.
High levels of TNF-α have been demonstrated in rotenone-treated rats. The microglia activated by rotenone may be responsible for the release of TNF-α, which causes neuronal degeneration. Our results suggest that TNF-α plays a role in sustaining dopaminergic degeneration in chronic Parkinsonism. Treatment with a high dose of PIR (200 mg/kg) decreased striatal TNF-α level which can be corroborated with the results obtained by Al-Bahrani, et al.  Overall, the results of the present study suggest that PIR may have a role in inhibition of neuronal loss mediated by pro-inflammatory cytokine, which may initiate a new aspect of the role of nootropic drugs in the treatment of chronic Parkinsonism. 
A unique mechanism of VIN is its ability to alter the rheological properties of red blood cells by increasing the erythrocyte's deformability, and also inhibiting platelet aggregation. These two actions combine to enable the blood cells to better penetrate the small vessels of the cerebromicrovasculature, thus delivering adequate supplies of glucose, oxygen and other energy substrates and cell nutrients which can improve neurocognitive health and function. VIN has also been shown to facilitate the release of oxygen from hemoglobin and increase blood oxygenation.  PIR also changes the physical properties of membranes, and enhances membrane fluidity. 
These results suggest that chronic treatment with PIR and VIN exhibit neuroprotective effect in rotenone-induced Parkinsonian rats. The effect of PIR has been suggested to arise from its anti-inflammatory properties whereas VIN is likely to have an antioxidant action. Therefore, these agents can be investigated thoroughly in clinical trials for use in Parkinson's disease.
| » Acknowledgments|| |
We acknowledge Dr. Amina A. Dessouki, Assistant Professor of Pathology, Faculty of Veterinary Medicine, Suez Canal University, for helping in the histopathological examination. We are very grateful for the generous gift of VIN from Medical Union Pharmaceuticals (Abo Sultan, Egypt) and PIR from Sigma Pharmaceutical Co. (Quesna, Egypt).
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