الفهرس 
INTRODUCTION & AIM OF THE WORKOnly 14 pages are availabe for public view
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Abstract
Second-generation antipsychotics have been substantially used in treatment of psychiatric disorders during the past decade, among them, olanzapine was shown to have well-known efficacy to treat schizophrenia with greater tolerability, while the metabolic side effects induced by its use have raised the need to exploring further mechanisms to ameliorate these side effects.
Accumulated evidence has shown a potential relationship between antipsychotic drug affinity for specific receptors and metabolic side effects. In particular, H1 receptor antagonism has been identified as the main contributor to olanzapine -induced body weight gain/obesity side effects. Recently, co-treatment with betahistine (a histamine H1 receptor agonist H3 receptor antagonist) has been shown to improve OLA-induced weight gain.
It is also hypothesized that oxidative stress may play a role in SGA induced side effects, in addition it has been implicated in the pathophysiology of schizophrenia
Since betahistine has a very high safety profile it has a huge potential for chronic management of antipsychotic-induced weight gain and obesity in schizophrenia
Therefore, inspection further to the betahistine role would be helpful when using the isolation rearing model, a valid, realistic simulation of schizophrenia in animals.
Aim of the work:
In the present work explore if the co-treatment with betahistine and olanzapine could maintain therapeutic effects of olanzapine, beside preventing its side effects regarding hyperlipidemia and insulin resistance, in chronic socially isolated Sprague-Dawley rats, Also the study stepped further towards investigating the effect on cognition and whether or not these changes were related to altering oxidative state.
Study design:
46 Male Sprague-Dawley Rats were divided into 5 main groups:
1. Control group (social reared) animals: (n=9); received standard rat chow and tap water for 8 weeks.
2. Isolated reared (further subdivided into untreated and vehicle treated (received 0.0001% acetic acid i.p. in the last 3 weeks)): (n=10); isolated for 8 weeks.
3. Isolated reared Betahistine treated rats: (n=9); isolated for 8 weeks; received betahistine 8mg/kg/day i.p. in the last 3 weeks.
4. Isolated reared Olanzapine treated rats: (n=9); isolated for 8 weeks; received olanzapine 6mg/kg/day i.p. in the last 3 weeks.
5. Isolated reared Betahistine +Olanzapine treated rats: (n=9); isolated for 8 weeks; received betahistine and olanzapine concomitantly in the last 3 weeks.
All rats received standard rat chow for 8 weeks
Outcome measures:
In-vivo studies
• Behavioral Tests:
1. three-chamber Social Interaction Test:
a) Session 1 (Sociability Index Measures)
b) Session 2 (Social Preference Indices)
2. Morris water maze (MWM):
a) Latency to Reach Target Quadrant measured by (sec)
b) % Of Time Spent in Target Quadrant Day 6
• Body weight measured by (gm)
Biochemical Studies
• Lipid profile (LDL, total cholesterol and triglycerides)
• Glucose homeostasis (fasting blood glucose, fasting blood insulin and HOMA-IR index)
• Malondialdehyde (Serum MDA)
• Serum reduced glutathione (GSH)
The Results Could Be Summarized as Follows
• Behavioral Tests:
1. three-chamber Social Interaction Test:
a) Session 1 (Sociability Index Measures)
Exposure to isolation rearing has induced schizophrenia signs manifested by significant decline in sociability index (SI) in social interaction test (Session I), this decline was reversed by chronic treatment with olanzapine (OLA) alone or combined with betahistine (BTH+OLA).
b) Session 2 (Social Preference Indices)
Isolated-reared rats performed as well as social-reared rats, exploring the novel object significantly more than the familiar object, chronic treatment with OLA decreased exploring the novel object significantly more than the familiar object and adding betahistine to OLA didn’t alter this defect.
2. Morris water maze (MWM):
Isolation rearing did not affect the rate of acquisition in visuospatial learning task, the same has been observed with socially-reared rats.
animals treated chronically with olanzapine, alone or combined with betahistine, demonstrated significant cognitive deficits in spatial learning and memory, as revealed by increase in latency to reach the hidden platform in the acquisition phase in MWM, there was also increase in latency time to enter the target quadrant and decline in time spent in it in the probe trial in the 6th day.
Chronic administration for 3 weeks of betahistine had no improvement effect on olanzapine-induced cognitive deficit.
• Body weight measured by (gm)
Chronic treatment with OLA induced significant increase in body weight in rats from the 7th till the 8th week in comparison to isolated reared group.
Chronic treatment with BTH reversed the increase in body weight in olanzapine-treated rats.
Chronic treatment with BTH alone without combination, significantly reduced body weight in isolated reared rats from the 6th till the 8th week.
• Biochemical Studies
a) Lipid profile and glucose homeostasis
Chronic treatment with OLA was associated with metabolic changes manifested by significant increase in blood levels of TC, TGL and LDL. It was also associated with significant increase in fasting insulin, fasting glucose and HOMA-IR, and chronic treatment with BTH+OLA significantly reduced all metabolic changes induced by olanzapine.
b) Oxidative stress markers
Exposure to isolation rearing has produced significant decrease in the serum GSH, that returned to the level of the social-reared group following administration of betahistine alone, with no change in MDA level.
Chronic treatment with olanzapine has increased serum MDA and decreased serum GSH.
Chronic treatment with BTH+OLA combination significantly modulated olanzapine-induced changes in serum MDA and serum GSH.
Correlation analyses were made for changes in serum oxidative stress markers’ levels versus both serum lipids and HOMA-IR; the findings demonstrate significant positive correlation of changes in GSH levels with improvement (decrease) in metabolic side effects i.e., the higher the GSH levels, the less side effects. The reverse was found for MDA level changes.