Dr. Peter J Cavnar

Neutrophils are pivotal innate immune cells, serving as the body's first line of defense against bacterial and fungal infections. They rapidly extravasate from the bloodstream to sites of inflammation followed by chemokine-induced integrin activation and firm adhesion. A deficiency in neutrophils, known as neutropenia, severely compromises immune function, leading to recurrent and potentially life-threatening infections. Emerging research suggests an interplay with neurotransmitters like dopamine (DA) potentially modulating neutrophil behavior. Studies have indicated that dopamine can influence various immune responses, including neutrophil chemotaxis and expression of adhesion molecules, suggesting an anti-inflammatory role. This experiment aims to further analyze the impact of dopamine on neutrophil adhesion. By treating neutrophils, incubated with Calcein AM, with varying concentrations of DA, we will observe changes in their adhesive properties, thereby providing insights into the neuro-immunomodulatory effects of dopamine on critical neutrophil functions.

Atypical antipsychotics are widely used for the treatment of mental and behavioral disorders such as bipolar disorder, obsessive-compulsive disorder, and schizophrenia. However, these drugs can occasionally induce neutropenia or agranulocytosis, characterized by a significant reduction in circulating neutrophils, the primary white blood cells responsible for immune responses. This drug-induced neutropenia poses a considerable risk of life-threatening infections. However, the precise mechanism by which atypical antipsychotics induce neutropenia remains unclear. This study investigates the effects of four atypical antipsychotics, namely - aripiprazole, clozapine, olanzapine, and quetiapine - on the human neutrophil model cell line HL-60. These drugs, which modulate dopamine receptor signaling alongside other mechanisms, were analyzed for their effects. Among these, aripiprazole - but not the others - uniquely induced apoptosis in a dose-dependent manner, accompanied by an increased expression of pro-apoptotic genes - BAK, BCL10, and caspase-3. Moreover, our study elucidates that while differentiated HL-60 cells express D1-like and D2-like dopamine receptors, aripiprazole's cytotoxic effects appear to operate through dopamine-independent pathways and significantly reduce phosphorylated Src family kinase levels. Our results align with previous studies suggesting that aripiprazole exhibits cytotoxic properties in neutrophils. Nevertheless, further investigations are warranted to investigate the mechanisms underlying aripiprazole-induced apoptosis in neutrophils.

Neutrophils are the immune system's first line of defense against infections and bacteria, and they alone make up about 70% of the leukocytes in the human body. The lack of neutrophils is called neutropenia and can be caused by certain medications. The atypical antipsychotic aripiprazole is seen in a small subset of patients to be a cause of this drug induced neutropenia. Dopamine has been found to be present in many tissues like bone marrow, suggesting that immune cells are regulated by dopamine. However, there is differing reports on whether human neutrophils have the five dopamine receptors, and it is unknown if the cell line PLB-985, a human myeloid leukemia cell line that can be differentiated into neutrophils using DMSO, will have the dopamine receptors. The results found that of five dopamine receptors, DRD3 and DRD5 were found to be present on the cell, and that Aripiprazole's effect is through a dopamine receptor independent mechanism.

This paper describes the synthesis of several halogenated S and Se heterocycles and tests their biological activity by measuring the effects on the myeloid leukemia cell line, PLB-985 cells. We report that select compounds exhibit significant increases in mitochondria membrane potential and increased oxidative stress in PLB-985 cells. In addition, several compounds caused cytotoxicity at high cell densities. Our results contribute to the foundational knowledge of different S and Se containing compounds and their possible impacts on human cells.