ABSTRACT
The neurobiological and neurochemical mechanisms underlying the pathophysiology of bipolar disorder are complex and not yet fully understood. From circadian disruption to neuroinflammation, many pathways and signaling molecules are important contributors to bipolar disorder development, some specific to a disease subtype or a cycling episode. Pharmacological agents for bipolar disorder have shown only partial efficacy, including mood stabilizers and antipsychotics. The purinergic hypothesis for bipolar disorder emerges in this scenario as a promising target for further research and drug development, given its role in neurotransmission and neuroinflammation that results in behavioral and mood regulation. Here, we review the basic concepts of purinergic signaling in the central nervous system and its contribution to bipolar disorder pathophysiology. Allopurinol and novel P2X7 receptor antagonists are promising candidates for treating bipolar disorder. We further explore currently available pharmacotherapies and the emerging new purinergic targets for drug development in bipolar disorder.
Subject(s)
Antipsychotic Agents , Bipolar Disorder , Affect , Anticonvulsants/therapeutic use , Antimanic Agents/therapeutic use , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Bipolar Disorder/drug therapy , HumansABSTRACT
Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic signaling system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a non-selective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20 mg/kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment did not affect VPA-induced upregulation of P2X4 and P2Y2 receptor expression in the hippocampus, and P2X4 receptor expression in the medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic signaling modulation in behavioral, molecular, and immunological aberrations described in VPA model, and indicate that the purinergic signaling system might be a potential target for pharmacotherapy in preclinical studies of ASD.
Subject(s)
Autistic Disorder/drug therapy , Disease Models, Animal , Prenatal Exposure Delayed Effects/drug therapy , Purinergic Antagonists/administration & dosage , Receptors, Purinergic , Valproic Acid/toxicity , Animals , Anticonvulsants/toxicity , Autistic Disorder/chemically induced , Autistic Disorder/metabolism , Brain/drug effects , Brain/metabolism , Female , Locomotion/drug effects , Locomotion/physiology , Male , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/metabolism , Rats , Receptors, Purinergic/metabolism , Suramin/administration & dosageSubject(s)
Depression/metabolism , Receptor, Adenosine A2A/metabolism , Suicide/psychology , Adenosine/metabolism , Depression/physiopathology , Depressive Disorder/metabolism , Depressive Disorder/physiopathology , Humans , Impulsive Behavior/physiology , Receptor, Adenosine A2A/drug effects , Receptors, Purinergic/metabolism , Suicidal IdeationABSTRACT
The work with midbrain dopaminergic neurons (mDAN) differentiation might seem to be hard. There are about 40 different published protocols for mDAN differentiation, which are eventually modified according to the respective laboratory. In many cases, protocols are not fully described, failing to provide essential tips for researchers starting in the field. Considering that commercial kits produce low mDAN percentages (20-50%), we chose to follow a mix of four main protocols based on Kriks and colleagues' protocol, from which the resulting mDAN were engrafted with success in three different animal models of Parkinson's disease. We present a differential step-by-step methodology for generating mDAN directly from human-induced pluripotent stem cells cultured with E8 medium on Geltrex, without culture on primary mouse embryonic fibroblasts prior to mDAN differentiation, and subsequent exposure of neurons to rock inhibitor during passages for improving cell viability. The protocol described here allows obtaining mDAN with phenotypical and functional characteristics suitable for in vitro modeling, cell transplantation, and drug screening.
