Sonic hedgehog pathway as a new target of atypical antipsychotics: Revisiting of amisulpride and aripiprazole effects in a rat model of schizophrenia

Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development

“…Additionally, their administration was associated with reduced neuroinflammation, as indicated by decreased levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α), whose effects were correlated with Hh levels. These findings were demonstrated in animal models of schizophrenia with associated cognitive dysfunction induced by a social isolation protocol [ 22 ]. Furthermore, Hh signalling has been associated with neurogenesis, as it enhances BDNF secretion, which has been considered a neuropathophysiological correlate of psychosis since reduced BDNF levels have been reported in the serum of patients with first-episode psychosis compared to healthy subjects [ 51 , 52 ].…”

“…Three animal studies were focused on the involvement of the Hh signalling in models of schizophrenia or on genes correlated with the risk of schizophrenia. Abdelfattah et al [ 22 ] exposed male Wistar rats to social isolation and treated them with amisulpride or aripiprazole, finding that treatment reversed cognitive dysfunction induced by social isolation alongside changes in the Hh pathway and astrocyte activity. Boyd et al [ 24 ] manipulated Sonic Hedgehog (Shh) signalling in zebrafish embryos, observing disruptions in disc1 expression and oligodendrocyte precursor cell specification, suggesting a potential link between aberrant Hh signalling and mental disorders.…”

“…Additionally, post-mortem studies on patients with schizophrenia have highlighted altered astrocytic activity, reporting significant changes in astrocyte morphology, density, and dysregulated expression of astrocyte-defining cellular markers associated with a significant increase in the levels of glial fibrillary acidic protein (GFAP) [ 57 , 58 ]. These results may be linked to studies demonstrating that social isolation correlates with the dysregulation of GFAP, BDNF, and D1 receptors, which are highly expressed in the prefrontal cortex and involved in controlling working memory and cognitive functions [ 22 ]. Reduced activation of D1 receptors has been associated with cognitive dysfunction and negative symptoms of schizophrenia [ 59 ].…”

“…Treatment with amisulpride and/or aripiprazole reversed these changes, enhancing Hh pathway components, dopamine-1 receptors, and BDNF and decreasing astrocyte activity and inflammatory markers. These findings suggest a favourable role for amisulpride and aripiprazole in regulating the expression of D1 receptors and BDNF and the Hh signalling pathway activation, leading to cognitive and neurogenesis improvements [ 22 ]. Amisulpride and/or aripiprazole were found to stimulate the Hh signalling pathway, as their administration resulted in a significant increase in concentrations of Patched (Ptch), Glioma-associated oncogene homolog 1 (Gli1), BDNF levels, and D1 receptor mRNA, along with a significant decrease in Glioma-associated oncogene homolog 3 (Gli3) concentrations.…”

“…Finally, we included 8 articles [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ] focusing on the involvement of the Hh pathway in the neuropathophysiology of schizophrenia and treatment response to antipsychotic drugs (see PRISMA flow diagram, Figure 2 ).…”