RESUMEN
Schizophrenia is a serious mental health disorder that confers one of the highest mortality rates of all psychiatric illnesses. Although the disorder's psychotic symptoms are treatable with conventional antipsychotics, they remain incurable. Moreover, medication adherence is poor, and individuals with schizophrenia choose to self-medicate with illicit substances, including cannabis. It is well-established that the delta-9-tetrahydrocannabinol (delta-9-THC) component of cannabis elicits psychotomimetic effects at high doses; worsens schizophrenia-related psychosis; commonly develops into cannabis use disorder in individuals with schizophrenia; and increases the risk of earlier-onset schizophrenia symptoms in those harboring genetic susceptibility. However, individuals with schizophrenia commonly use cannabis and cannabis derivatives such as cannabidiol (CBD). These products seem to alleviate psychotic symptoms and relieve adverse side effects of antipsychotic medications. Therefore, one notion that has gained traction is the potential utility of cannabis-derived cannabidiol (CBD) as adjunct treatment to reduce schizophrenia-associated psychosis and other symptoms. Currently, preclinical and clinical data remain inconclusive. The present review distinguishes the mechanisms underlying schizophrenia-associated vs. cannabis-induced psychosis; reviews the evidence for delta-9-THC-mediated exacerbation vs. CBD-mediated amelioration of schizophrenia-associated psychosis; and describes potential approaches for incorporating CBD into schizophrenia therapeutic regimen in a safe and efficacious manner.
RESUMEN
Matrix metalloproteinases (MMPs) are zinc- and calcium- dependent endopeptidases that play pivotal roles in many biological processes. The expression of several MMPs in the central nervous system (CNS) have been shown to change in response to injury and various neurological/neurodegenerative disorders. While extracellular MMPs degrade the extracellular matrix (ECM) and regulate cell surface receptor signaling, the intracellular functions of MMPs or their roles in CNS disorders is unclear. Around 23 different MMPs are found in the human genome with overlapping function, making analysis of the intracellular role of human MMPs a daunting task. However, the fruit fly Drosophila melanogaster genome encodes only two MMPs: dMMP1 and dMMP2. To better understand the intracellular role of MMPs in the CNS, we expressed Green Fluorescent Protein (GFP)- tagged dMMPs in SH-SY5Y neuroblastoma cells and C6 glioblastoma cell lines. Lipofection of GFP-dMMPs in SH-SY5Y cells enhanced nuclear rupture and reduced cell viability (coupled with increased apoptosis) as compared to GFP alone. In non-liposomal transfection experiments, dMMP1 localizes to both the cytoplasm and the nucleus whereas dMMP2 had predominantly cytoplasmic localization in both neural and glial cell lines. Cytoplasmic localization demonstrated co-localization of dMMPs with cytoskeleton proteins which suggests a possible role of dMMPs in cell morphology. This was further supported by transient dMMP expression experiments that showed that dMMPs significantly increased neurite formation and length in neuronal cell lines. Inhibition of endogenous MMPs decreased neurite formation, length and ßIII Tubulin protein levels in differentiated SH-SY5Y cells. Further, transient expression experiments showed similar changes in glial cell morphology, wherein dMMP expression increased glial process formation and process length. Interestingly, C6 cells expressing dMMPs had a glia-like appearance, suggesting MMPs may be involved in intracellular glial differentiation. Inhibition or suppression of endogenous MMPs in C6 cells increased process formation, increased process length, modulated GFAP protein expression, and induced distinct glial-like phenotypes. Taken together, our results strongly support the intracellular role that dMMPs can play in apoptosis, cytoskeleton remodeling, and cell differentiation. Our studies further reinforce the use of Drosophila MMPs to dissect out the precise mechanisms whereby they exert their intracellular roles in CNS disorders.