Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer’s disease (sAD). Intracerebroventricular (ICV) ...injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD.
Abstract 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.
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.
A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we ...evaluated the effects of the PPAR-α agonist fenofibrate (100mg/kg) and PPAR-γ agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD.
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 21days 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 22days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.
•The intranigral infusion of 6-OHDA was able to promote a depressive-like behavior.•6-OHDA-lesioned rats exhibited a reduction in the levels of hippocampal serotonin and striatal dopamine.•Animals ...that received 6-OHDA showed a decrease in swimming time and consumption of sucrose.•There is a correlation between hippocampal serotonin and time swimming and sucrose consumption.•There is a correlation between striatal dopamine levels and immobility time in the forced swim test.
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.
•Streptozotocin caused deficits in short-term spatial and recognition memory.•Streptozotocin decreased adult neurogenesis and increased neuroinflammation.•Curcumin prevented streptozotocin-induced ...impairments in recognition memory.•Curcumin did not prevent streptozotocin-induced impairments in spatial memory.•Curcumin did not improve adult neurogenesis and neuroinflammation.
Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer’s type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV–STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test – ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin-positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis.
•The model of 6-OHDA-induced parkinsonism in rats results in anxiety-like behaviour.•In contrast with dopamine and norepinephrine, serotonin significantly increased in the amygdala in the ...6-OHDA-lesioned rats.•Anxiety in PD may be related to a dysregulation of monoamines in areas such as amygdala, prefrontal cortex and striatum.
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.
Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and ...piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.
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.
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