الفهرس 
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Abstract
Sulpiride a selective antagonist at dopamine D2 and D3 receptors. This action dominates in doses exceeding 600 mg daily. In doses of 600 to 1, 600 mg, sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared with chlorpromazine is only 0.2 (1/5). In low doses (50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine receptors accounting for some antidepressant activity and a stimulating effect. Therefore, these doses were used as a second line antidepressant. Additionally, it alleviates vertigo.
Amisulpride functions primarily as a D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 2.2 nM and 2.4 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory pre-synaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason a low dose amisulpride is used to treat dysthymia. Amisulpride and its parentsulpiride have been shown to bind to and activate the GHB receptor at doses that are used for therapeutic purposes.Though it has long been widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride.It has recently been shown that it also acts as a potent antagonist at the 5-HT7 receptor (Maitre et al., 1994). Other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor that show antidepressant properties, probably as in the role of the 5-HT7 receptor in antidepressant effects of amisulpride.
The dentate gyrus is part of the hippocampus and/or hippocampal formation as some texts include the latter structure in the former or vice versa. The dentate gyrus is thought to contribute to the formation of new episodic memories (Amaral et al., 2007). Being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats. Other sites include the olfactory bulb and cerebellum (Graziadei, 985). Granule cells within the molecular layer of the dentate gyrus receive the hippocampal formation’s major excitatory input from the cortex. This input is primarily made up of signals from layer II of the entorhinal cortex and is the first connection of the trisynaptic loop, the hippocampal circuit.
Brain-derived neurotrophic factor also known as BDNF is a protein (Binder et al., 2004), that in humans is encoded by the BDNF gene (Jones et al., 1990). BDNF is a member of the neurotrophin family of growth factors which are related to the canonical Nerve Growth Factor. Neurotrophic factors are found in the brain and the periphery. It plays a crucial rule in a promoting neuronal integrity and synaptic plasticity like long term potentiation, learning and memory (Barolcelly et al., 2010). Preclinical and clinical studies revealed reduction of the serum BDNF levels in untreated depressed patients and their normalization after treatment with antidepressants.BDNF level is proposed to be a biomarker of illness and depressant response (Sen et al., 2008).
Antigen KI-67 also known as Ki-67 or MKI67 is a protein in humans that is encoded by the MKI67 gene (antigen identified by monoclonal antibody Ki-67). Antigen KI-67 is a nuclear protein that is associated with and may be necessary for cellular proliferation. Furthermore, it is associated with ribosomal RNA transcription (Harrington et al., 2008). Inactivation of antigen Ki-67 leads to inhibition of ribosomal RNA synthesis. So it is used as cell marker.The Ki-67 protein (also known as MKI67) is a cellular marker for proliferation.
The objective of the present study is to evaluate the antidepressant properties of Amisulpride over a range of doses in two procedures namely the Forced Swim Test (FST) (Porso et al., 1978) and immune-histopathology of KI67. Neurogenesis is a peculiar form of neuroplasticity with a potential role for cognition and behavior (Loal et al., Cia et al., 2008; Tomas et al., 2007). The studies of Kempermann et al. (2008) suggested that adult Hippocampal neurogenesis may be altered in various immune-psychatric disorders like major depression and neurodegenerative disorders.The study is designed to investigate the effect of high versus low dose of Amisulpride on Hippocampal neurogenesis in male Wistar Han albino rats.
There is an increase of immobility time in seconds in CSS group compared with Control group. Treatment with oral Amisulpride for 21 days in doses of 10mg/kg/day and 20mg/kg/day result in statistically significant decrease in immobility time as compared with CSS group. while amisulpride 5 mg is insignificant in decreasing immobility time. Climbing time is decreased in CSS group compared with Control group, while there is statistically significant increase in climbing time with treatment with oral Amisulpride of 10 and 20mg/kg/day compared with CSS group.
In this study there was a statistically significant decrease in BDNF level in (pg/ml) in CSS group compared with Control group, while treatment with oral amisulpride in 5, 10 and 20 mg/kg/day result in significantly statistically increase in BDNF value.
There is decrease in granulosa cell layer thickness in CSS group compared with Control group. Also there is significant increase in cell proliferation in treatment with oral amisulpride 5, 10 and 20mg/kg/day compared with CSS group. Number of KI67 positive cells is statistically decreased in SVZ in CSS group compared with Control group. Also treatment with oral amisulpride 5, 10 mg/kg/day result in significant increase in KI67 immunostained cells in SVZ, with the maximum increase with 20 mg/kg/day compared with CSS. On the contrary, CSS group results in a significant decrease in number of KI67 positive cells in SGZ compared with Control group, while treatment with oral amisulpride 10 and 20 mg/kg/day result in statistically insignificant increase in number of positive KI67 cells compared with CSS group.
Conclusion:
Treatment of rats with amisulpride in doses of 10 and 20 mg/kg/day orally for 21 days resulted in a significant decrease in immobility and increase of climbing time compared with CSS group indicating an antidepressant like behavior and its role in hippocampal neurogenesis, as evident by increase in granulosa cell thickness in DG and increase in number of Ki 67 positive cells in SVZ in DG.
Future research:
1- Assessing CASPASE 3 immunostained cells in SVZ and SGZ as a marker of neurogenesis.
2- Further research on low doses of amisulpride on neurogenesis.
3- Assessing metabolic and cardiovascular side effects of amisulpride in comparison with other antipsychotics.
4- Teaching the concept of neurogenesis with factors influencing it including BDNF protein.
5- Demonstrating effect of amisulpride on neurodegenerative diseases as alzeheimer in old patients.