Research reportNeurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson’s disease
Introduction
Parkinson’s disease (PD) is a complex neurodegenerative chronic disorder affecting the dopaminergic system [1]. The prevalence of PD increases with age, reaches a maximum around 75–80 years and involves about 1.5% of people aged 65 or older [2]. PD affects mainly the substantia nigra pars compacta (SNc), where wide dopaminergic degeneration happens [3]. The degeneration of dopaminergic (DA) neurons, results in loss of the dopaminergic inputs to the striatum by the nigrostriatal pathway. Degeneration in this pathway causes functional disruption of basal ganglia’s circuitry and the development of several physical symptoms of PD, such as resting tremors, muscle rigidity, akinesia and postural instability [4]. The main etiology of PD has not been known in the most cases. However, genetic factors, oxidative stress, infections, apoptosis, excitotoxicity as well as head trauma and vascular disease have all been suggested as possible risk factors [5], [6].
Although at first cognitive impairment in Parkinson’s disease was ignored for many years but recent evidence has shown that cognitive changes associated with PD have a clear impact on the quality of patients’ life [7], [8]. Numerous studies have demonstrated that that the basal ganglia also plays role in learning and memory processes [9]. This concept is in agreement with studies showing the critical effects of basal ganglia dopamine on striatal synaptic plasticity [10]. In addition, many cognitive deficits that are initially showed by PD patients are similar to those observed in patients with prefrontal cortex lesions. It can be the result of disconnected current from the basal ganglia and dysfunction in the different neuronal loops connecting the prefrontal cortex, basal ganglia, and thalamus [11], [12].
Combinational therapy with DA precursor (L-dopa) and DOPA- decarboxylase inhibitors is still the most effective treatment in the field of motor symptoms, but this type of therapy has no effect on cognitive defects in PD [13].
According to the influence of the cognitive disorders on the quality of PD patients’ life, it is the subject of interest to evaluate whether cognitive disorders can also be studied in animal models of PD.
The results of previous studies have indicated a higher prevalence and incidence of PD in men than women. This gender difference indicates an efficacy of sex hormones on the development of PD [14], [15]. Current studies have shown that steroid hormones can affect the survival of neuronal cells, synaptic formation and plastic changes in adult’s nervous system [16]. Furthermore, increasing evidence suggests that neurosteroids have neuroprotective properties on the CNS and PNS. It has been reported that progesterone (PROG) as a neurostroid decreases behavioral disorders symptoms in a rodent model of traumatic brain injury [17]. In addition, it has been reported that neurosteroids can reduce neurological deficits after spinal cord injury and also promote functional recovery after middle cerebral artery occlusion in rodents [18], [19]. Moreover, neurosteroids display neuroprotective effects against dopaminergic degeneration induced by MPTP and methamphetamine in rodents [20].
Allopregnanolone (Allo) (3-hydroxy-5-pregnan-20-one), a PROG metabolite that generated de novo in the central nervous system (CNS), is also known to be a potent endogenous positive modulator in CNS or PNS [21]. In human PD subjects the serum and CSF levels of Allo are lower that those in healthy people [22]. It has been demonstrated that Allo synthesis enzymes genes expression decreases in post-mortem brain specimens of PD patients [23]. These findings suggest that a lower level of Allo in brain may promote the progression of degenerative disease such as PD [24].
Recent studies have demonstrated that Allo reverses the degradation of thyrosin hydroxylase (TH) expressing cells in basal ganglia of MPTP-lesioned mice [25] and induces the neurogenesis in a mouse model of Alzheimer’s disease (AD) [24]. It is also reported that neurosteroids can affect motor components and reproductive behaviors in rat and hamster model of 6-OHDA-induced parkinsonism [26].
Here, we centered our interest around cognitive symptoms in Parkinson’s disease and the purpose of the current study was to examine whether allopregnanolone has a protective role against cognitive disorder in 6-OHDA-induced Parkinsonism in rats.
Section snippets
Animals
Adult male Wistar rats (200–250 g) were used to test the hypothesis. All experimental protocols and treatments were approved by the Ethics Committee of Kerman Neuroscience Research Center (Ethics Code: EC/93). We attempted to minimize the inconvenience for the animals in all the steps of the study. Animals were kept (each cage consisted of four rats) with ad libitum access to food and water under controlled temperature (23 ± 1 °C) and 12-h light–dark cycle. The rats were randomly divided into
Spatial learning and memory
During the learning phase, animals in control and sham groups easily learned to find the invisible platform as showed by the reduction in their swimming distance (Fig. 1A) and escape latency (Fig. 1B) across blocks of training. 6-OHDA-treated animals (lesion group) could not find the platform. However, a significant decrease in the swimming distance was observed in animals that had 20 mg/kg Allo (Lesion + Allo20) (P < 0.01) as compared with lesion animals in the third block of the test (Fig. 1A).
Discussion
Parkinson’s disease is a progressive neurodegenerative disorder and its current therapeutic strategies are ineffective [4]. It has been shown that cognitive deficits became an important part of patient management because such deficit in turn gives rise to a poor quality of life and economic burden [33].
Previous studies have shown that female rats have fewer functional deficits than males following brain frontal cortex injury [34]. This gender difference suggests a neuroprotective role for sex
Conclusion
present study showed that Allo strongly enhances learning and memory in 6-OHDA model of Parkinson’s disease in rats. The results provide some interesting cues regarding the effects of Allo and its useful area of research in order to study non-motor stages in animal models, and the possible utility of Allo as a neuroprotector agent.
Acknowledgments
This work was supported by funds from Kerman Neuroscience Research Center (#93/37), Kerman University of Medical Sciences. The authors would like to thank the editor and two anonymous reviewers for their critical comments on an earlier version of this manuscript.
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