Neurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson’s disease

Highlights

• The effects of allopregnanolone were assessed on the PD-induced cognitive disorders.

• Moris water maze, novel object recognition and object location tasks were used.

• Allopregnanolone significantly improved the cognitive impairment induced by 6-OHDA.

• Present study strongly supports the procognitive property of allopregnanolone in PD.

Abstract

Cognitive deficits have an extensive influence on the quality of life of the Parkinson’s disease (PD) patients. Previous studies have shown that lack of steroid hormones have an important role in the development of PD. Therefore, in this study the effects of neurosteroid allopregnanolone (Allo) on the PD-induced cognitive disorders were assessed. To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat’s substantia nigra. Allo (5 and 20 mg/kg, orally) were administered on the day after the 6-OHDA injection and continued during the entire treatment period (two months). Cognitive behaviors were assessed by Moris water maze (MWM), novel object recognition (NOR) and object location tasks. The data indicated that Allo significantly improved the 6-OHDA-induced cognitive impairment which revealed by the reduction of time spent to find out platform (escape latency) and the increase of retention time in MWM test and also with increase in the exploration index in NOR and object location tasks. Present study strongly supports the pro-cognitive property of allopregnanolone in PD.

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.