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Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists have received much attention in research because of their neuroprotective and anti-inflammatory effects that reduce cell death and halt the progression of neurodegeneration. Thus, this study observed the pioglitazone effects on the main inflammatory markers after 6-hydroxydopamine (6-OHDA) lesion. The effects of a 5-day administration of the PPAR-γ agonist pioglitazone (30 mg/kg) in male Wistar rats that received bilateral intranigral infusions of 6-OHDA. After surgery, the rats were evaluated in the open-field test on days 1,7,14, and 21. Immediately after the behavioral tests on day 21, the rats were euthanized, and the substantia nigra was removed to analyze the expression of nuclear factor κB (NF-κB) and IκB by western blot. To immunohistochemical, animals were intracardially perfused, with brain removal that was frozen and sectioned, being selected slices of the SNc region to detect tyrosine hydroxylase (TH) immunoreactivity, microglia activation (Iba-1) and NF-κB translocation in the nucleus. Pioglitazone protected rats against hypolocomotion and 6-OHDA-induced dopaminergic neurodegeneration on day 7. Decreases in the microglial activation and the NF-κB expression were observed, and the p65 activation was inhibited. These results suggest that pioglitazone may be a potential adjuvant for the treatment of Parkinson`s disease because of its effects on pathological markers of the progression of neurodegeneration.

The most common features of Parkinson's disease (PD) are motor impairments, but many patients also present depression and memory impairment. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to be effective in patients with treatment-resistant major depression. Thus, the present study evaluated the action of ketamine on memory impairment and depressive-like behavior in an animal model of PD. Male Wistar rats received a bilateral infusion of 6 μg/side 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNc). Short-term memory was evaluated by the social recognition test, and depressive-like behaviors were evaluated by the sucrose preference and forced swimming tests (FST). Drug treatments included vehicle (i.p., once a week); ketamine (5, 10 and 15 mg/kg, i.p., once a week); and imipramine (20 mg/kg, i.p., daily). The treatments were administered 21 days after the SNc lesion and lasted for 28 days. The SNc lesion impaired short-term social memory, and all ketamine doses reversed the memory impairment and anhedonia (reduction of sucrose preference) induced by 6-OHDA. In the FST, 6-OHDA increased immobility, and all doses of ketamine and imipramine reversed this effect. The anti-immobility effect of ketamine was associated with an increase in swimming but not in climbing, suggesting a serotonergic effect. Ketamine and imipramine did not reverse the 6-OHDA-induced reduction in tyrosine hydroxylase immunohistochemistry in the SNc. In conclusion, ketamine reversed depressive-like behaviors and short-term memory impairment in rats with SNc bilateral lesions, indicating a promising profile for its use in PD patients.

Objectives To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. Methods Male Wistar rats (weighing 280–300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). Key findings Saxagliptin impaired the memory of animals in the sham group. Conclusions Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD.

Parkinson’s disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia , but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50-kHz ultrasonic vocalizations , gait impairment (catwalk test), and depressive-like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50-kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion-induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6-hydroxydopamine induced subtle motor and non-motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson’s disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson’s disease.

Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiological mechanism that underlies depressive symptoms that are often observed in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA-lesioned rats, which might contribute to its antidepressant-like effect.

Anxiety in Parkinson's disease may represent a physiological reaction to the development of other symptoms during disease progression. However, evidence suggests that the incidence of anxiety disorders in Parkinson's disease may be related to neurochemical changes. The present study addresses the question whether dopamine, noradrenaline and serotonin levels in brain structures related to Parkinson's disease and anxiety are responsible for anxiety-like behavior by using an animal model of parkinsonism based in the bilateral injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in the substantia nigra pars compacta. For this, one day after the injection of 6-OHDA, the animals exhibited hypolocomotion and a lower frequency of rearings in the open field test, which was spontaneously reversed on the last day of motor assessment (day 21). The 6-OHDA injection also induced anxiety-like behavior in the elevated plus maze and contextual fear conditioning test (day 21 and 24, respectively). Neurochemical analysis showed a reduction of dopamine and norepinephrine levels in the striatum, prefrontal cortex, and amygdala. In addition, while the serotonin levels were reduced in the striatum and prefrontal cortex, it was increased in the amygdala. The present study indicates that the model of 6-OHDA-induced parkinsonism in rats induced an anxiety-like behavior that may be related to a dysregulation of neurotransmitter systems in brain areas involved with anxiety such as the amygdala, prefrontal cortex and striatum.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiology and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addition, anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100mg/kg 1h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, respectively. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.

Idiopathic Parkinson's disease is a neurodegenerative disorder that affects approximately 1 % of the population over 55 years of age. The disease manifests itself through motor and nonmotor symptoms induced mainly by the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The possible mechanisms involved in this pathology include mitochondrial dysfunction, neuroinflammation, and oxidative stress. The present study evaluated the effects of the nonselective cyclooxygenase inhibitor ibuprofen on motor and depressive-like behavior induced by rotenone in rats. Rotenone (2.5 mg/kg, i.p., for 10 days) decreased tyrosine hydroxylase immunoreactivity in the SNpc, and ibuprofen treatment (15 mg/kg, p.o., for 22 days) blocked this impairment. We also found that rotenone-induced motor deficits (hypolocomotion) and depressive-like behavior, and ibuprofen was able to reverse these deficits. In addition to motor and nonmotor behaviors, we evaluated oxidative stress induced by rotenone. Rotenone administration depleted glutathione levels in the hippocampus and reduced catalase activity in both the hippocampus and striatum. Post treatment with ibuprofen blocked the depletion of glutathione induced by rotenone and increased the basal levels of this antioxidant in the striatum. Ibuprofen also restored catalase activity. The neuroprotective effects of ibuprofen against toxicity induced by rotenone appear to be attributable to its antioxidant properties, in addition to cyclooxygenase inhibition.

There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect.

Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 μg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.

The present study investigated the neurochemical, motor and cognitive effects of pioglitazone in a rat model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the first experiment, we administered MPTP, and 1 h later administered a single oral dose of pioglitazone (5, 15 and 30 mg/kg). The following day, we performed the open-field test and neurochemical dose response curve. We demonstrated that 30 mg/kg of pioglitazone was capable of restoring striatal dopamine (DA) concentrations and motor behaviors. A second experiment was conducted to test the effects of two protocols (acute and chronic) of pioglitazone (30 mg/kg) administration in the open-field test, two-way active avoidance task and in the DA and metabolites levels. The acute protocol consisted of a single oral administration 1 h after MPTP, whereas the chronic protocol was performed with daily administrations starting 1 h after MPTP and ending 22 days after that. Results showed that neither protocol was able to reverse the cognitive impairment promoted by MPTP. We also demonstrated that acute treatment generated some level of neuroprotection, as confirmed by the absence of DA reduction in the group treated with pioglitazone in comparison to the sham group. By contrast, chronic treatment leaded to a reduction of striatal DA, close to MPTP administration alone. These findings suggest that acute administration of pioglitazone (30 mg/kg) was more efficient in generating beneficial effects on motor behaviors and in striatal DA levels. Nevertheless, we failed to demonstrate that pioglitazone administration improved performance on a dopamine-related cognitive task after MPTP.

Parkinson's disease is a chronic neurological disease characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta. Melatonin is a powerful antioxidant agent secreted by the pineal gland which has numerous physiological functions and seems to exert an important neuroprotective effect. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model has been used to understand the pathophysiology of the disease because of its capacity to mimic biochemical and histological features observed in Parkinson's disease. This study investigated the effect of pretreatment with melatonin (50 mg/kg) on MPTP-lesioned animals 24 h and 7 days after neurotoxin infusion using the open-field test, two-way avoidance task and immunohistochemistry. Twenty-four hours after lesioning, the MPTP+vehicle group exhibited hypolocomotion and significant loss of tyrosine hydroxylase-immunoreactive cells, whereas no differences in these parameters were observed in lesioned animals receiving melatonin. Seven days after surgery, the MPTP-lesioned rats did not show hypolocomotion compared to control animals, while there was a significant dopaminergic neuronal loss. In the two-way avoidance task, MPTP-treated animals presented a cognitive deficit compared to the control groups and melatonin administration did not repair this defect. The present results suggest that melatonin reduces neuronal loss in the MPTP animal model of Parkinson's disease.

Different Parkinson's disease (PD) animal models reproduce the early phase of the disease, which deny the possible existence of a synergic effect of consecutive insults to the dopaminergic neurons. We proposed a novel protocol of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nigrostriatal lesion, which consists in repeated MPTP intranigral administrations intending to differentiate effects of a single lesion in relation to repeated lesions. For this purpose, a schedule of 3-day intervals between the MPTP administrations, totalizing 3 infusions in 9 days were adopted. A persistent locomotor deficit was produced after the 2nd infusion, remaining until the last time-point. Tyrosine hydroxylase (TH) immunoreactive neurons were reduced in 50% 1 day after the 1st infusion and the neuronal loss remained constant even after the 2nd and 3rd MPTP infusions. In parallel, (TH) protein expression in the substantia nigra pars compacta (SNpc) revealed to be a sensitive target for MPTP, once it was found to be down-regulated immediately after the 1st MPTP exposure until the last time-point. These findings corroborate the concept of an early phase model of PD elicited by MPTP even when this neurotoxin was used according to the protocol currently proposed. The current protocol provided relevant insights about TH expression and irreversible locomotor impairment.

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD. A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. Nesta revisão, foram abordadas evidências de envolvimento do processo inflamatório e uma possível utilidade terapêutica de drogas antiinflamatórias na DP.

Depression is one of the most common psychiatric symptoms in patients with Parkinson’s disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21 days. In the forced swim test, the 6-OHDA + saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham + saline. In the sucrose preference test, the 6-OHDA + piroxicam group exhibited no reduction of sucrose preference compared with the sham + saline, with significant effects of treatment and time and a significant treatment × time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA + saline group and not changed in the 6-OHDA + piroxicam group when compared with the sham + saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

The present study investigated the effects on general activity, COX-2 and TH protein expression of intranigral neurotoxins LPS, MPTP or 6-OHDA infusion in rats. Results indicate that LPS produced an increase in locomotion frequency (3 and 7 days after surgery) and a strong up-regulation of COX-2 protein 16 and 24 h after surgery, as observed in the substantia nigra (SN). The MPTP model generated impairment in locomotion frequency 24 h after surgery. Besides, MPTP caused a marked up-regulation in COX-2 protein observed in the SN 16 h after surgery. Moreover, the 6-OHDA model produced severe motor impairment indicated by the decrease in locomotion (24 h) and rearing (24 h, 3 and 7 days) frequencies and also an increase in latency (24 h, 3 and 7 days) and immobility (24 h and 3 days) times. We also demonstrated an up-regulation of COX-2, which occurred in the SN 4-24 h after surgery. TH protein did not appear to be reduced in the striatum in the groups lesioned with the neurotoxins. In contrast, the TH content of SN was significantly reduced in the groups lesioned with the very same neurotoxins. For all the models analyzed, we observed no statistical differences in the expression of COX-2 in the striatum along the time-points. The results of the present study suggest that COX-2 induction patterns differ in function of the neurotoxin tested. Such time-dependent induction has been found to be relatively constant, a fact of great significance considering the importance of the neuroinflammatory process in Parkinson's disease.

The present study investigated the effects of intranigral MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) infusion on rats treated with phosphatidylserine and evaluated in two memory tasks and on striatal dopamine levels. The results indicated that MPTP produced a significant decrease in the avoidance number in comparison to sham-operated and non-operated rats submitted to a two-way avoidance task. MPTP-lesioned rats exhibited an increase in the latencies to find the platform in cued version of the water maze in comparison to sham-operated and non-operated animals. The tested toxin reduced striatal dopamine levels in comparison to sham-operated and non-operated groups. A final surprising result was that phosphatidylserine was unable to reverse the cognitive deficits produced by MPTP or the reduction of striatal dopamine levels. In conclusion, the data suggest that MPTP is a good model to study the early impairment associated with Parkinson's disease and phosphatidylserine did not improve the memory impairment induced by MPTP.

The effects of dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, were studied on dopamine-related behaviors induced by reserpine treatments. This study focuses on behavioral syndromes that may used as models for Parkinson's disease, or tardive dyskinesia, and its response after glutamatergic blockage. Reserpine (1 mg/kg), administered once every other day for 4 days, produced increases in orofacial dyskinesia, tongue protrusion and vacuous chewing in mice, which are signs indicative of tardive dyskinesia. Reserpine also produced tremor and catalepsy, which are signs suggestive of Parkinson's disease. MK-801 (0.1 mg/kg), administered 30 min before the observation test, prevented the vacuous chewing movements, tongue protrusions and catalepsy induced by reserpine. However, MK-801 injection produced a significant increase of tremor in reserpine-treated mice. Reserpine (1 mg/kg), administered 90 min before the test and followed by apomophine injection (0.1 mg/kg) 5 min before the test, did not produce oral dyskinesia in mice. On the other hand, reserpine induced increases in tremor and catalepsy compared to control mice. MK-801 (0.1 mg/kg) administration attenuated the catalepsy and tremor induced by reserpine. Pretreatment with reserpine (1 mg/kg) 24 h before the observation test produced increases in vacuous chewing movements and tongue protrusion, as well as increases in tremor and catalepsy, whereas MK-801 (0.1 mg/kg) injection 90 min before the test reversed the effects of reserpine. These results show that reserpine produces different and abnormal movements, which are related to dose and schedule employed and can be considered as parkinsonian-like and tardive dsykinesia signs. The glutamatergic blockage produced by NMDA can restore these signs, such as vacuous chewing movements, tongue protrusions, catalepsy and tremor according to the employed model.

Parkinson׳s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5 mg/kg) or its vehicle. 24 h later, they were intraperitoneally treated with melatonin (10 mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD.

The effects of phosphatidylserine (PS) were studied in rats treated with reserpine (1 mg/kg) immediately after training in the passive avoidance task. In experiment I, phosphatidylserine (25 mg/kg) was administered 30 min before or immediately after training. Acute pre- or post-treatment with phosphatidylserine was effective in reversing the amnestic effect of reserpine in test trials performed 24 h and 1 week after training. Experiment II was performed to determine if the long-term pretreatment with phosphatidylserine (25 mg/kg) for 7 days is able to protect the rats against the amnestic effects of reserpine in this task. The data show that phosphatidylserine reverses the impairment induced by reserpine in trials performed 24 h and 1 week after training. These results indicate that the memory deficits associated with catecholamine depletion caused by reserpine can be attenuated by acute pre- or post-training or by long-term pretreatment with this phospholipid.

It has been previously shown that oxcarbazepine (OXCBZ), a keto-analogue of carbamazepine, exhibits an antidepressive-like effect profile in the learned helplessness and forced swimming test (FST). Since carbamazepine possesses dopaminergic effect, the present study was carried out to evaluate the extent to which the antidepressive effect of OXCBZ might be mediated by dopaminergic system. Thus, the effects of OXCBZ in haloperidol-induced catalepsy and apomorphine-induced stereotypy were studied. The anti-immobility effect of OXCBZ in the FST was also evaluated in haloperidol pre-treated rats. OXCBZ (40 and 80 mg/kg, i.p.) dose-dependently reduced the catalepsy induced by haloperidol (2.0 mg/kg, i.p.). Moreover, OXCBZ (80 mg/kg, but not 20 or 40 mg/kg, i.p.) increased the intensity of apomorphine-induced stereotypy (0.6 mg/kg, s.c.). Finally, it was observed that the combination of OXCBZ (80 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) antagonized the anti-immobility effect of OXCBZ and further increased the immobility time when compared to haloperidol alone. Haloperidol alone (0.5 or 1.0 mg/kg) did not change the immobility time. Thus, these results suggest that OXCBZ could enhance dopaminergic neurotransmission, which might mediate its antidepressive-like effect.

Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40–70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with “emotional” impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions.

Background Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson’s disease (PD). In this study, we investigated the motor and depressive-like behaviors associated to neurochemical alterations induced by a novel protocol of rotenone administration. Methods In the first experiment, we adopted the paw test to characterize an effective dose of rotenone able to promote nigrostriatal toxicity. In the second experiment, control and rotenone 2.5 mg/kg groups were injected ( ip ) for 10 consecutive days. Results This test indicated that intraperitonial ( ip ) rotenone at 2.5 and 5.0 mg/kg promoted a significant neurotoxicity to striatum and nucleus accumbens. However, only 2.5 mg/kg of rotenone was associated to a negligible mortality rate. Open-field tests were conducted on 1, 7, 14 and 21 day after the last day of treatment and showed an important locomotor impairment, confined to 1 and 7 day. Besides, rotenone affected dopamine levels and increased its turnover in the striatum. Modified forced swim test (performed on 22 day) and sucrose preference test (performed on 14 and 21 day) demonstrated that rotenone produced impairments in the swimming and immobility. In parallel, increments in the serotonin and noradrenaline turnovers were observed in the striatum and hippocampus of the rotenone group. Conclusions These data suggest important participations of serotonin and noradrenaline in depressive-like behaviors induced by rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting about 1% of the population older than 60 years. Classically, PD is considered as a movement disorder, and its diagnosis is based on the presence of a set of cardinal motor signs that are the consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta. There is now considerable evidence showing that the neurodegenerative processes leading to sporadic PD begin many years before the appearance of the characteristic motor symptoms, and that additional neuronal fields and neurotransmitter systems are also involved in PD, including olfactory structures, amygdala, caudal raphe nuclei, locus coeruleus, and hippocampus. Accordingly, adrenergic and serotonergic neurons are also lost, which seems to contribute to the anxiety in PD. Non-motor features of PD usually do not respond to dopaminergic medication and probably form the major current challenge in the clinical management of PD. Additionally, most studies performed with animal models of PD have investigated their ability to induce motor alterations associated with advanced phases of PD, and some studies begin to assess non-motor behavioral features of the disease. The present review attempts to examine results obtained from clinical and experimental studies to provide a comprehensive picture of the neurobiology and current and potential treatments for anxiety in PD. The data reviewed here indicate that, despite their high prevalence and impact on the quality of life, anxiety disorders are often under-diagnosed and under-treated in PD patients. Moreover, there are currently few clinical and pre-clinical studies underway to investigate new pharmacological agents for relieving these symptoms, and we hope that this article may inspire clinicians and researchers devote to the studies on anxiety in PD to change this scenario. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action.

Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.

The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject’s world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson’s disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson’s disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson’s disease patients.

The potential neuroprotective or neurotoxic effects of 3,4-dihydroxyphenylalanine (L-DOPA) are yet to be understood. We examined the behavioral, immunohistochemical, tyrosine hydroxylase (TH) expression and neurochemical parameters after an intranigral administration of L-DOPA (10 μM) in rats.. L-DOPA elicited a 30.5% reduction in dopaminergic neurons, while 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 μg μL−1) produced a 53.6% reduction. A combined infusion of MPTP and L-DOPA generated a 42% reduction of nigral neurons. Motor parameters revealed that both the MPTP and L-DOPA groups presented impairments; however, the concomitant administration evoked a partial restorative effect. In addition, MPTP and L-DOPA separately induced reductions of TH protein expression within the substantia nigra. In contrast, the coadministration of MPTP and L-DOPA did not demonstrate such difference. The striatal levels of dopamine were reduced after MPTP or L-DOPA, with an increased turnover only for the MPTP group. In view of such results, it seems reasonable to suggest that L-DOPA could potentially produce dopaminergic neurotoxicity.

A doença de Alzheimer é a patologia neurodegenerativa mais freqüente associada à idade, cujas manifestações cognitivas e neuropsiquiátricas resultam em deficiência progressiva e incapacitação. A doença afeta aproximadamente 10% dos indivíduos com idade superior a 65 anos e 40% acima de 80 anos. Estima-se que, em 2050, mais de 25% da população mundial será idosa, aumentando, assim, a prevalência da doença. O sintoma inicial da doença é caracterizado pela perda progressiva da memória recente. Com a evolução da patologia, outras alterações ocorrem na memória e na cognição, entre elas as deficiências de linguagem e nas funções vísuo-espaciais. Esses sintomas são freqüentemente acompanhados por distúrbios comportamentais, incluindo agressividade, depressão e alucinações. O objetivo deste trabalho foi revisar, na literatura médica, os principais aspectos que envolvem a doença de Alzheimer, como as características histopatológicas, a neuroinflamação e a farmacoterapia atual.

Dopamine (DA) has, as of late, become singled out from the profusion of other neurotransmitters as what could be called a key substance, in the regulation of the sleep-wake states. We have hypothesized that dopaminergic D(2) receptor blockage induced by haloperidol could generate a reduction or even an ablation of rapid eye movement (REM) sleep. Otherwise, the use of the selective D(2) agonist, piribedil, could potentiate REM sleep. Electrophysiological findings demonstrate that D(2) blockage produced a dramatic reduction of REM sleep during the rebound (REB) period after 96 h of REM sleep deprivation (RSD). This reduction of REM sleep was accompanied by an increment in SWS, which is possibly accounted for the observed increase in the sleep efficiency. Conversely, our findings also demonstrate that the administration of piribedil did not generate additional increase of REM sleep. Additionally, D(2) receptors were found down-regulated, in the haloperidol group, after RSD, and subsequently up-regulated after REB group, contrasting to the D(1) down-regulation at the same period. In this sense, the current data indicate a participation of the D(2) receptor for REM sleep regulation and consequently in the REM sleep/SWS balance. Herein, we propose that the mechanism underlying the striatal D(2) up-regulation is due to an effect as consequence of RSD which originally produces selective D(2) supersensitivity, and after its period probably generates a surge in D(2) expression. In conclusion we report a particular action of the dopaminergic neurotransmission in REM sleep relying on D(2) activation.

The present study investigated the effects of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib (Bextra™) in the prevention of motor and cognitive impairments observed in rats after an intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model of the early phase of Parkinson's disease. The treatment with parecoxib (10 mg/kg) administered prior to the surgery and daily (2 mg/kg) for the subsequent 21 days, prevented the MPTP-treated rats from presenting decreased locomotor and exploratory behavior, increased immobility, and impairment while performing the cued version of the Morris water maze. Furthermore, parecoxib treatment also significantly prevented the reduction of tyrosine hydroxylase protein expression in the substantia nigra (7, 14 and 21 days after surgery), and in the striatum (14 and 21 days after surgery) as immunodetected by western blotting. These results strongly suggest that parecoxib exerts a neuroprotective effect on motor, tyrosine hydroxylase expression, and cognitive functions as it prevents their impairments within the confines of this animal model of the early phase of Parkinson's disease.

The aim of the present study was to develop an animal model for the study of depressive symptoms associated with Parkinson's disease (PD). Mice treated intraperitoneally with reserpine (RES), 2.0 and 1.0 mg/kg, or its vehicle (VEHIC) were submitted to the sucrose solution (2%) consumption test (a model employed to mimic the depressive symptoms found in PD) and to the spontaneous locomotor activity test (a model employed to mimic the motor impairment found in PD). All animals were submitted to both tests. Twenty-four hours after treatment, only RES 2.0-treated animals showed a significantly decreased preference for the sucrose solution (mean +/- S.E.M. RES 2.0 = 54.4 +/- 4.1%, RES 1.0 = 68.5 +/- 2.5%, VEHIC = 62.3 +/- 4.1%). There was no significant difference among groups in water, sucrose or total fluid consumption. Locomotor activity was significantly decreased by both RES doses (number of beam interruptions: RES 2.0 = 59.9 +/- 11.4, RES 1.0 = 82.2 +/- 9.7, VEHIC = 116.8 +/- 8.2). Thus, RES 2.0 administration to mice induced depressive (anhedonia) and motor (decreased locomotor activity) symptoms of depression-PD association. This suggests that the RES model shows an important aspect of face validity for the depressive state associated with PD, i.e., phenomenological similarities between the model and the situation being modeled.

In the present study we investigated the effects of co-administration of GM(1) (15.0 mg/kg, twice daily, for 30 days) and haloperidol (1.0 mg/kg, twice daily, for 30 days), as well as the effects of a 5-day treatment with this dose of GM(1) after withdrawal from haloperidol in rats. The animals were evaluated in the open-field test and apomorphine-induced stereotyped behaviour. The results show that GM(1) was able to attenuate dopaminergic supersensitivity evaluated by the locomotion frequency at 24 and 48 h after the withdrawal from haloperidol. On the other hand, rearing frequency was changed neither by haloperidol nor by GM(1.) In haloperidol-treated rats immobility time differs from 30 min observation session in comparison with the following sessions after the withdrawal from neuroleptic. Apomorphine-induced stereotyped behaviour produced a significant increase in scores of haloperidol-withdrawn rats. GM(1) did not modify the haloperidol effects and did not change the dopamine receptor affinity to apomorphine 100 h from abrupt neuroleptic withdrawal.

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

1. 1- The effects of monosialoganglioside GM 1 were studied on a new model of tardive Dyskinesia I.e., the frequency of spontaneous tongue protrusions in rats repeatedly treated with reserpine. 2. 2- Rats were co-treated with vehicle (VEH) or reserpine (RES) (0.1 mg/kg, sc, every other day) and saline (SAL) or GM 1 (5 mg/kg, ip, every day) for 30 days and observed for tongue protrusions on days 10, 20 and 30. 3. 3- During each test day animals of the RES+SAL group exhibited an increase in tongue protrusions relative to rats of the VEH+SAL group. However, rats of the RES+GM 1 group showed an increased frequency of tongue protrusions only on day 10, when compared to animals of the VEH+SAL group. There were no significant differences in tongue protrusion frequency between the VEH+GM 1 and the VEH+SAL groups. 4. 4- These results differ from previous studies which reported a facilitatory effect of GM 1 coadministration on conventional behavioral animal models of tardive dyskinesia. The possibility is raised that GM 1 attenuates the reserpine-induced increase in tongue protrusions through its protective effect on glutamate/oxidative stress neurotoxicity.