Exploring Standardized Zembrin® Extracts from the South African
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Internationa Journal of Complementary & Alternative Medicine Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential treatment in Schizophrenia Abstract Mini Review Converging evidence suggests that Disrupted in Schizophrenia (DISC-1) is a (Phosphodiesterase Subtype-4) plays a crucial role in neurodevelopment and SimonVolume 6Chiu Issue1,4 5*, - Hana2017 Raheb1, Kristen neuro-inflammationrecognized risk gene in for schizophrenia. schizophrenia. Serotonin The interaction has drawn of increasedDISC- with attention PDE-4 Terpstra1,5, Josh Vaughan1,6, Autumn for its role in modulating cognition function. Hence dual targeting Selective Carrie1,7, Michel Farina-Woodbury2, Yves 1,8 1,4 1 towards augmenting antipsychotics in schizophrenia. Translational studies show Bureau , Zack Cernovsky , Jirui Hou , 3 8 thatSerotonin the family Reuptake of mesembrane-related site (SSRI) and PDE-4 alkaloids may offer isolated novel from therapeutic the South paradigm African John Copen , Mariwan Husni , Vladimer Badmeav9, Mujeeb Shad10, Zach Suntras8 4 allosteric site. The promising findings warrant a proof-of-concept randomized and Nigel Gericke11 controlledplant: Sceletium study Zembrintortuosum extract have inbeen schizophrenia. shown to hit dual targets: SSRI and PDE- 1Lawson Health Research Institute, Canada 2Department of Psychiatry, University of Puerto Rico, USA Keywords: Schizophrenia; DISC-1 gene; Serotonin; Phosphodiesterase; Zembrin 3Department of Psychiatry, University British Columbia: University of Victoria medical campus, Canada 4Department of Psychiatry, University of Western Ontario, Extract Canada 5Nursing Program, University of Toronto Faculty of Nursing, Canada Introduction 6Biomedical Sciences Honors Program, University Western Ontario, Canada In schizophrenia treatment (SCZ) while the second generation of 7Kinesiology Honors Program, University Western Ontario, atypical antipsychotics are associated with fewer extra pyramidal Canada 8Northern Ontario Medical School, Thunderba, Canada motor side effects, the atypical antipsychotics prove to be no 9Formerly Director of Medical and Scientific Affairs, USA st superior than the 1 generation of antipsychotics. The overall long 10Oregon Health & Science University, USA term outcomes in area of social and vocational domains remain 11Department Psychiatry, Medical Director and founding unfavourable [1]. Cognitive impairment precedes the emergence Director of HG&H Pharmaceuticals (Pty) Ltd, South Africa of positive and negative symptoms and appears to persist *Corresponding author: Simon Chiu, Lawson Health concludes that the negative outcomes are strongly related to the severitythroughout of impairedthe course neuro-cognition of the disorder (INC). [2,3]. TheExpert recent consensus NIMH Research Institute 268 Grosvenor Street; Lab FB125, London Ontario N6A 4V2 Canada, Email: initiative, MATRICS (Measurement and Treatment Research to Received: March 12, 2017 | Published: May 01, 2017 Improve Cognition in Schizophrenia) outlines a strategic plan to address the issue through identifying promising molecular targets for future drug development [4,5]. Pharmacological interventions targeting various neurotransmitter networks: GABA, glutamate, experience the negative consequences of negative symptoms [8]. dopamine (DA), serotonin (5-HT), norepinephrine have met with Ahigh recent as 58% systematic of the reviewschizophrenia of the pharmacological outpatients are treatmentsestimated toin negative symptoms [9] highlight the new approaches in targeting: 1) enhancing N-methyl-D-aspartic acid (NMDA) function through The issue of enduring negative symptoms carries equal mixed findings [6]. glycine binding site or glycine uptake inhibitor; 2) metabotropic weight in determining the overall quality of life in schizophrenia glutamate receptor: mGluR2/3) allosteric modulator; 3) nicotinic cholinergic receptor. It has become a high priority to adopt a new entity characterized by the presence of primary enduring negative approach to address the issues of neuro-cognition and negative symptoms,population. appears The primary to be relatively deficit syndrome, refractory definedto the newer as a atypicaldisease symptoms. Recently, there has been increased interest in the antipsychotics [7]. Primary negative symptoms are common emerging role of cAMP signaling in modulating neuro-cognition schizophrenia [10]. in around 26% of the schizophrenia patient population and as Submit Manuscript | http://medcraveonline.com Int J Complement Alt Med 2017, 6(5): 00203 Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum Copyright: in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential ©2017 Chiu et al. 2/7 treatment in Schizophrenia DISC-1 gene and PDE: Role in schizophrenia decreased locomotor activity and attenuated prepulse inhibition Converging gene evidence suggests that the gene, Disrupted- accompaniedchanges equivalent by reduced to negative dopamine symptoms and and serotonin cognition turnover deficits: [23]. Transgenic mice with forebrain restricted expression one of the important group of risk genes for schizophrenia [10,11]. in-Schziophrenia-1 (DISC1, MIM605210) is highly implicated as The DISC locus was originally discovered in a large Scottish oligodendrocyte (OLG) differentiation and OLG gene expression family pedigree with a balanced translocation (q42.1, q14.3); the of mutant human DISC1 (ΔhDISC1) showed abnormalities in SCH, bipolar disorder (BPD) and severe recurrent depression [12]. deficits [24] premature OLG differentiation and increased chromosomal translocation co-segregates significantly not only in Since then, various genetic association studies have replicated defectsproliferation in SCH. of their progenitors were identified. This finding the original translocation family study. Genetic variants: single suggests that PDE may be involved in remodelling of myelination working memory and information processing in rodent species nucleotide polymorphisms (SNP) have been identified in a Rolipram, the PDE4 inhibitor, improved memory consolidation, large sample from European population [13]. A meta-analysis avoidance, delayed arm water and visual -spatial tasks, working of 9 different schizophrenia samples from different European memorysubject to and a varietyinformation of cognitive [25-28] .tasks: In the macaqueradial arm monkey maze, species,passive populations identified 50 SNPs and found evidence for a common interval with the DISC1intron 4-6 defining the schizophrenia risk. of DISC-1 in encoding a multifunctional scaffolding protein rolipram antagonizedimproved objectphencyclidine retrieval (PCP)-induced performance hyperactivity suggesting nd Significant advances have been messenger: made to delineatecyclic adenosine the role positive interaction with executive function [26]. Furthermore, monophosphate (cAMP) signaling via interactions with inhibition and facilitated extinction of cocaine-induced place that specifically regulates 2 preferenceand cognitive [29,30]. deficits, The reversed mechanism amphetamine of the pro-cognitive -induced pre- action pulse of body of evidence in support of the regulatory role of DISC-1in neurodevelopmentphosphodiesterase and4 (PDE4)neuro plasticity[10,14]. [15].There Dysregulation is a growing of synaptic plasticity due to SCZ at risk gene may be the underlying neuronsPDE-4 inhibitor, in layer rolipram, VI [31]. may Rolipram be related was toactive the co in -expression the sensori- of pathophysiology of SCZ. DISC-1 regulates neurogenesis, neuronal motorPDE-4 withgating DARPP test [31] -32 whichin D1 receptor-positive may be explained cortical by the pyramidalenhanced migration, dendritic arborization, and integration of cortical DARPP-32 phosphorylation invoked by D1 receptor activation in and hippocampal neurons. The family of phosphodiesterase shown to bind with DISC1 [12]. Two DISC-1 strains of mutant pro-cognitivethe frontal cortex. strategy Recent in SCZtranslational and neurodegenerative studies of PDE disorders: have also micehydrolyzes have been intracellular demonstrated cAMP, toMore exhibit importantly, reduced bindingPDE4B has capacity been focused attention on PDE-10 and PDE-2A as putative targets for is in Phase II/III clinical trials in SCZ. Taken together, elevated Alzheimer dementia [33,34]. None of the PDE -10A or PDE-2 and affinity to PDE-4B while exhibiting behavioral changes There has been growing interest in the crucial role of cAMP- resembling SCZ and depression symptoms [16]. cAMP contributes towards cognition deficits mediated through intracellular second messengers: cAMP and cGMP, in regulating inthe SCZ. prefrontal cortex and targeting PDE-4- phosphorylated cAMP response element binding protein (CREB), coupled with the Response-Element-Binding protein (CREB) (19) can be beneficial multiple gene expressions [17-19]. Both cAMP and cGMP signal Converging evidence suggests that cognitive impairment cascades are involved in neuronal survival, apoptosis, and synaptic strength and plasticity and neural network connectivity in CNS. In this respect the superfamily of 11 phosphodiesterases currentlyin schizophrenia indicated is forrelated the totreatment neuro-inflammation. of chronic obstructive The anti- pulmonaryinflammatory disease action of(COPD) the prototypal is relevant PDE-4 to inhibitor, our understanding roflumilast, sensing(PDE)