ABSTRACTBackground Researchers previously showed that patients

ABSTRACT

Background: Researchers previously showed that patients with neurodevelopmental disorders usually suffer from lower bone mineral density with unknown etiology. Until now, there is limited information about the effects of Risperidone as atypical antipsychotic (AA) drugs on bone strength in mice with neurobehavioral disorders induced by LPS. Therefore, we aimed to evaluate the effects of Risperidone on biomechanical, histological and molecular aspects of bones in mice with LPS induced neurobehavioral disorders compared to normal matched for age ones.

Design/methods: Male offspring from normal and LPS-induced dams were extracted, and were randomly distributed into five groups; 1- PBS: received an equal volume of PBS solution on day 28-56 postnatal 2-Vehicle: received an equal volume of 0.

1% acetic acid(RIS solvent) solution on day 28-56 postnatal 3- LPS; this groups were exposed to LPS prenatally and received only an equal volume of PBS solution on day 28-56 postnatal.4- RIS: This group received orally 0.

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75 mg/kg of freshly prepared RIS solution on day 28-56 postnatal 5- LPS+RIS: This group were exposed to LPS prenatally and received orally 0.75 mg/kg of freshly prepared RIS solution on day 28-56 postnatal.

At the end of experiments (PD=56), we conducted a series of tests including behavioral test (open field and three chamber test), biomechanical test and immunohistological and molecular(qPCR) tests for bone evaluation in male offspring mice aged 56 days.

Results: Our results revealed significant reductions in cortical bone stiffness, energy absorption, microhardness and a tensile modulus in LPS+RIS mic than typically developing control ones.

The immunohistological analysis also revealed that the numerical density of osteocalcin-positive cells was significantly decreased in LPS+RIS groups compared to other groups. Furthermore, LPS+RIS mice had fewer RUNX2 and OSTEOCALCINE gene expression. And also RES and LPS mice had a fewer percentage of expression in RUNX2 and OSTEOCALCINE than typically developing controls.

Conclusions: These results demonstrated that Risperidone as atypical antipsychotic (AA) drugs results in significant alterations in the biomechanical integrity of bone in patients with neurobehavioral disorders induced by LPS.

Introduction:

Introduction: The brain and the immune system are inseparably related. The important role of the immune system in brain development and associated behavioral effects has been approved in many studies. Definitely, there are many neuropsychiatric disorders, with different neurodevelopmental etiologies, which have a dependence on immune dysfunction. A relation between perinatal infection and neurodevelopmental disorders, like Autism Spectrum Disorder(ASD), has been suggested in many types of research. production of high levels of pro-inflammatory cytokines, like interleukins IL-1 and IL-6, in the maternal or fetal immune system have been related with irregular fetal brain development and an increased danger of neurodevelopmental disorders. Lipopolysaccharide (LPS), Which is formed from the cell wall of the gram-negative bacteria, can be a good imitator of infection in many animal studies. Previous investigations have been showed that encountering with LPS in the perinatal period can enforce many biochemical and behavioral long-term alterations (like impaired communication and socialization and repetitive/restricted behaviors) in the brain. most of these behavioral abnormalities of prenatal immune encounter remain for a long time during individuals life, and just can be improved by antipsychotic pharmacotherapy. Risperidone, as an atypical antipsychotics, is one of the successful treatments for inhibition the occurrence of brain mechanical pathology and behavioral defects induced by prenatal infections. Precisely, treatment with this drug can Improve many brain-behavioral irregularities in children with neurodevelopmental disorders. The early years of life are a critical time for bone in the achievement of peak bone mass, an important determinant of future bone health. Factors that can affect bone development during Pre-puberty include genetics, nutritional status [particularly calcium, vitamin D and protein intake (Davies et al. 2005; Foo et al. 2009; Lehtonen-Veromaa et al. 2002)], exercise activity, endocrine alterations and use of specific medications. It is reported that children with neurodevelopmental disorders like ASD have an affinity to have lower spine BMD in areal dual X-ray absorptiometry (aDXA) than normal children. They have high rates of co-morbid neurologic and psychiatric illnesses, including epilepsy and mood disorders, which may be associated with increased cortisol levels, exacerbating the risk for low bone integrity (Greaves-Lord et al. 2009; Lopez-Duran et al. 2009; Sheth et al. 2008) These children may also be treated with many antipsychotic & anticonvulsant medications, some of which may impact vitamin D metabolism and bone integrity in different ways. (Chou et al. 2007; Pack et al. 2008). It remains unclear if neurodevelopmental disorders are considered by low bone mass or lifestyle (diets, exercises, Vit D deficiency, etc.) composed with antipsychotics pharmacotherapy might be the reason. Risperidone decreases dopamine and serotonin activity with inhibition of D2-dopamine receptors and 5HT2 serotonin receptors (Bishara and Taylor, 2008; Singh and O'Connor, 2009). So this drug can cause hyperprolactinemia which is linked to its effectiveness in antagonizing D2 receptors. bone mass can be affected by hyperprolactinemia induced-hypogonadism with increased bone resorption (Meaney et al., 2004; O'Keane, 2008). throughout oral risperidone treatment, long-term outcomes of hyperprolactinemia have been described. In the current research we exactly hypothesized that behavioral alterations would be induced in mice by prenatal LPS and that these changes could be ameliorated by treatment with risperidone and also to determine whether biomechanical, histological and molecular properties of the long bones in mice with behavioral abnormalities is significantly different than in controls & animals treated with risperidone. The objectives of this study were to examine the effects of chronic treatment with risperidone on these bone parameters in mice models of neurodevelopmental disorders induced by LPS.