The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease
Introduction
Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease, is mainly characterized by the progressive and selective depletion of dopamine synthesizing neurons in the substantia nigra (SN) pars compacta (Muramatsu and Araki, 2002). PD is more prevalent in men than in women by an approximate 3:2 ratio, and epidemiological evidence suggests that estrogen influences the onset and severity of disease-associated symptoms (Dluzen and McDermott, 2000). Accumulating evidence supports a modulatory role of estrogen in the brain and its importance in the normal maintenance of brain function during aging. Decreased levels of estrogen with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders (Doncarlos et al., 2009).
Estrogen has effects on several neurotransmitter systems in the brain. It is an important regulator of serotonergic, dopaminergic, and cholinergic neurons (Imamov et al., 2005).
The classical actions of estrogen are initiated by its binding to the nuclear steroid receptors; estrogen receptor-alpha (ERα) or beta (ERβ). ERα and ERβ are differentially expressed in the brain (Zhang et al., 2002). Estrogen actions via this genomic mechanism, which are necessarily slow, may include inhibition of apoptosis, suppression of inflammatory reactions, and modulation of neurotrophins and growth factors as well as neuronal structure and synapse formation(Taber et al., 2001). Estrogen also has rapid actions, occurring far too quickly for genomic mechanisms. These may include its antioxidant effects as well as enhancement of cerebral blood flow (Zhao and Brinton, 2007). These nongenomic effects probably occur via both plasma membrane receptors and non-receptor-mediated pathways (Alyea et al., 2008). Some actions, such as modulation of neurotransmitters, may occur by both genomic and nongenomic mechanisms (Taber et al., 2001).
But, since the potential benefits of estrogen therapy for the brain are counter balanced by negative, life-threatening risks in the periphery; a potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons (Cyr et al., 2002). The mechanisms by which SERMs act are not completely clear, however it is known that SERMs bind to the ERs and form ER complexes similar to the estrogen receptor–estrogen complexes. These complexes can then either promote gene transcription, similar to estrogen, become misfolded and prevent gene transcription, or become misfolded and promote a different set of gene transcription (Jordan and O'Malley, 2007).
There is still controversy regarding the estrogen receptor subtypes mediating estrogen effect on PD (D'Astous et al., 2004, Wang et al., 2003). Thus, the aim of the current study was to evaluate the possible role of estrogen as well as the SERMs; tamoxifen and raloxifene, in ovariectomized female rats in which nigral dopaminergic cell death was induced by striatal injection of 6-hydroxydopamine (6-OHDA). The current study also investigated whether an ER subtype is involved in the estrogen effect by assessing the effect of a selective ERα agonist, propyl-pyrazole-triol (PPT) and a selective ERβ, diarylpropionitrile (DPN), on behavioral and biochemical alterations in 6-OHDA-induced nigral dopaminergic cell death in rats.
Section snippets
Animal grouping
80 female Wister albino rats obtained from the Central Animal House of Faculty of Medicine (Alexandria University), weighing 200–250 g at the start of the experiment, were used. Rats were housed in groups of four animals per cage. They were maintained on a natural 12-h dark–light cycle and provided with free access to rat chow and water. The study protocol was approved by the Ethics Committee, Faculty of Medicine, Alexandria University. 10 animals were sham operated, while 70 animals were
Uterine weight
Uterine weights decreased after OVX and increased by oestradiol, tamoxifen, PPT, but by neither raloxifen nor DPN (Table 1, Fig. 1a).
Behavioral results
OVX resulted in significant behavioral alterations evidenced by significant increase in apomorphine-induced rotational behavior contra lateral full body turns/30 min. In addition, a significant decrease in number of steps in forehand and in backhand direction could be observed in OVX rats compared to sham-operated rats.
6-OHDA injection had significant effect in
Discussion
In the present study administration of 6-OHDA to rats resulted in various behavioral and biochemical alterations suggestive of PD. The 6-OHDA rat model has been, and continues to be, one of the most popular experimental models of PD when it comes to the preclinical testing of new symptomatic therapies, as well as neuroprotective strategies. The unilateral 6-OHDA-treated rat is perhaps the most widely studied preclinical model of PD, and the effects of this model on nigrostriatal dopamine are
Conflict of interest statement
No conflicts of interest.
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