Exploring Standardized Zembrin® Extracts from the South African

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 forschizophrenia. schizophrenia. . Serotonin The interaction has drawn of increased DISC- 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 impaired the course neuro-cognition of the disorder (INC). [2,3]. The Expert 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 review schizophrenia of the pharmacological outpatients are treatments estimated 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

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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 antagonized improved 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 and 4 (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 for related 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) widelythe intracellular distributed levels in theof cyclic mammalian nucleotides brain [20]. function There regulate and fine-tune the homeostasis of cAMP-cGMP via phenotypeof the emerging resembling role of PDE-4anti-depressant in cognition treatment [35]. Genetic exhibited knock- resistancedown of PDE-4D to depression enzyme: in PDE4dthe classical (-/-) Porsoltmice displayed force swim behavioral test and are 11 members of PDE- family: PDE-1, PDE-2, PDE-3, PDE -4, PDE-5, PDE-6, PDE-7, PDE-8, PDE -9, PDE-10 and PDE-11 with isoformstheir characteristic with multiple substrate-specificities, gene splice variants tissuethat encode distribution more in the hyperactivity of the acoustic startle response [36]. Rolipram thanand physiological50 proteins functions.expressed Thein mammalian PDE family cells. has a There total ofis 21in exhibits anti-depressant effect and reverses Aβ-induced cognitive vitro evidence that release of DISC-1-mediated transcription standsimpairment at the and cross-roads neuro-inflammatory of immune and cell apoptotic (microglia) responses activation in rats via PDE-4D or PDE-4B inhibition [37]. Cyclic AMP signaling to inhibit dopaminergic signaling [21]. High levels of cAMP during repression of PDE4D9 serves as a paradigm of feedback inhibition and inflammation. In the glia, pro-inflammatory cytokines are is consistent with the link of DISC1 with the negative impact of familyinvolved of ininterleukins regulating PDE-4-cAMPand alpha-tumor signaling necrosis in the factor glia; [38]. whereas The stress exposure impaired prefrontal cortex (PFC) function and stress in neurodevelopment [22]. cross-talksPDE-cAMP-cascade between can cytokine in turn production modulate cytokine and immune production: activation the

pathway. PDE inhibitors are active in models of positive and negative are part of the feedback loop coordinated through PDE-4-cAMP symptoms of SCZ. PDE-4B knockout mice exhibited behavioral

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Chiu S, Raheb H, Terpstra K, Vaughan J, Carrie A, et al. (2017) 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. Int J Complement Alt Med 6(5): 00203. DOI: 10.15406/ijcam.2017.06.00203 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. 3/7 treatment in Schizophrenia

Despite translational studies in support of the antipsychotic The cognitive enhancing effects of the key ingredients of serious adverse effects of nausea and vomiting have largely efficacy of rolipram in schizophrenia and depressive disorders;, Zembrin® extract are explained largely by the efficacy of alkaloids in competing for the PDE-4 binding. The chemical structures of limited further therapeutic development. A single dose-finding mesembrenone alkaloids are fully characterized (Figure I). In symptomsstudy in 6 recurredschizophrenic in parallel patients with found serious an nauseainitial improvementand vomiting the PDE assay system using the human recombinant PDE-4B [39].of psychotic Rolipram symptoms appeared during to exhibit the first anti-depressant week; however, activity psychotic in expressed in Sf9 cells), the extract Selenium tortuous (Zembrin®) selectively inhibited phosphodiesterase 4 (PDE4) with IC50 (inhibitory constant) value of 8.5μg/ml. Mesembrenone, a major majorZembrin depressive extract disorder and PDE- [40]. 4 allosteric modulator/5-HT wasalkaloid 17 times isolated more from potent the extract than mesembrine (Figure 1) was and the 34 most times active more in In South Africa, extracts from South African Reuptake inhibitor: activeinhibiting than PDE4 mesembenol. with an IC50 The IC50value values of <1μM for ( mesembrenone 44 ). Mesembrenone were succulent plant, Sceletium tortuosum, has been used for centuries 470NM, followed by mesembrine: 7800nM and mesembrenol: as an orally available indigenous medicine, and for promoting 10,000 nM. Structure-Activity Relationship (SAR) studies show well-being, enhancing mood and reducing stress [41-43]. The that cognition is likely to be selectively mediated via the long standardized extract S, tortuous: Zembrin extract was developed by HG&H Pharmaceuticals Ltd. Bryanston, South Africa. isoform of PDE-4D3.

Figure 1: Chemical structures of alkaloids isolated from Sceletium tortuosum: mesembrine, mesembrenol, mesembrenone, mesembranol.

-4 modulators in exhibiting concomitant serotonergic property. TheMesembrenone serotonergic property alkaloids of distinguish mesembrine from alkaloids other putative synergizes PDE seriousRolipram, side effects despite of itsnausea efficacy and in vomiting. SCH and Investigators depression models,explore with cAMP signal pathway in mediating the cognitive effects. matchingfail to advance the preferred to final phasesconformation of clinical at the trial regulatory because site of theof Mesembrine was found to be the most potent compound in binding of 1.4 nM. Mesembrenone and mesembranol were found to be HGPDE-4 & H with Pharmaceuticals the potential (Pty) candidates Ltd discovered in designing that a the series South of muchto the weakerserotonin in thetransporter 5-HT transport site (5-HT site site)in vitro with Hill coefficient AfricaPDE-4 legendary allosteric modulatorsplant, Sceletium [49]. tortuosum It is perhaps exhibited fortuitous intrinsic the of Selective Serotonin Reuptake Inhibitors (SSRI) in the treatment of anxiety and depressive disorders is well documented [44]. The efficacy [45]. emetic effects [41]. In this respect, the family of mesembrane- More recently escitalopram, the putative SSRI, has been shown to activity as a PDE-4 allosteric modulator but devoid of serious together, there is growing evidence to substantiate the role played modulatorsrelated alkaloids with fromtherapeutic Zembrin potentialextract find for the the respected treatment niche of byimprove serotonin cognition in decision and facilitate making post- process stroke within recovery the [46]. cognitive Taken in comparison with the group of patented PDE-4 allosteric domain of executive function [47]. High central serotonin levels are functionally associated with improved reversal learning, derivativeschizophrenia, of rolipram Alzheimer’s [52]. dementia and depression: EHT0202 enhanced attentional set shifting and response inhibition while (etiolate hydrochloride) [50]; L-454,560 [51]; GEBR-7-b, reducing delay discounting. Preliminary evidence suggests that drug development platform based upon serotonin receptor BBBThe (Blood-Brain functional Barrier) MRI (fMRI) to modify study the conducted functional inresponses Europe towardsdemonstrated environmental for the first cues time capable that Zembrin of generating passes fearthrough [53]. the In the treatment of schizophrenia [48]. subtypes: 5-HT (1), 5HT (4), and 5-HT (6) may hold promise for a double-blind, placebo-controlled, cross-over design, 16 healthy

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participants were scanned during performance in a perceptual- load and an emotion-matching task. The reactivity of the brain region, amygdala, to fearful faces under low perceptual load The subjective ratings of generalized well -being and positive conditions was attenuated after a single 25mg oral dose of Zembrin. “upliftedmood states spirits” in our and study better [56] copingagrees wellwith with stress a recent and depressing safety and tolerability study on Zembrin® in healthy subjects who reported showed that the amygdala-hypothalamus coupling was adversely affected.Follow-up This connectivity fMRI study analysis clearly onshows the that emotion S. tortuosum matching (later task events [57]. Furthermore, subjects taking Zembrin® reported formulated as the standardize Zembrin extract) attenuates the 1.14),improvement changed in to the 0.43 subjective (SD =0.93) quality at week of 3their (paired sleep t-test, on the t = HAM2.09, emotional responses towards subcortical threat circuitry. The -D subscale: the mean rating of sleep onset at baseline, 0.76 (SD = result is consistent with the action of Zembrin extract in dual treated group found an overall improvement in the quality of sleep. df = 20, p=0.049, 2-tailed). In both studies [53,56,57], Zembrin® in the rodent model of restraint-induced anxiety and behavioral was safe and well tolerated. There were no changes in blood stress,targeting S. SSRITortuosum and PDE-4 at the in lowerthe acute dosage anxiolytic of 5-10 effects. mg/kg Earlier, when In the three clinical studies in normal subjects [53]. Zembrin® given by the oral lavage, exerted a marginal anxiolytic effect [54]. group or the placebo group. Intriguing enough, the study led Species differences in dose-response relationship of Zembrin may bypressure, Neil et pulse, al. [57] temperature found that and the weight placebo in groupeither complainedthe Zembrin® of explain the discrepant findings. classedincreased as frequency“mild” and of “moderate” adverse events was quite than lowthe Zembrin® group. The incidence of treatment emergent adverse events (TEAE) (n=2)Gericke and dysthymia[55] reported with for co-morbid the first personalitytime on three disorder case studies (n=1) of Zembrin in patients diagnosed as majorst case, depression the male disorder patient responded to daily oral dosage of 50mg Zembrin tablet with movingThe pharmacologicalrats [58]. The effectsparadigm of Zembrin®of electropharmacogram in humans are and major depressive disorder. In the 1 consistent with the results of an EEG study in conscious freely symptoms: insomnia, anhedonia, and suicidal ideation and significant sustained reduction in relatively severe depressive (EPG) was used to characterize the actions of Zembrin®. As a symptoms were found. In the second case, the female patient drug.novel The neurophysiological electrical signals technique, were transmitted EPG consists via ofthe frequency wireless reportedmood fluctuations. that “her mood During had lifted, the first feeling week, more transient focused and anxiety less analysis of the field potentials in the presence of the active anxious” within 10 days of starting on 50mg Zembrin tablet. Her hypersomnia was also resolved, in the third case, the patient who neurotransmittermode and processed system using and aspectral Fast Fourier power Transformationwas evaluated was non-responsive to St. John’s Wort (hypericum perforatum) over(FFT). the The 8 frequency frequency ranges: ranges delta, are theta, sensitive alpha, tobeta1a, the specificbeta1b, extract reported improvement in her mood. She noted that her hypersomnia amounting to 14 hr per day was changed to her normal pattern of 8hrs/day. beta1abeta2, gammawhich correlated power. Zembrin® with activation at the oral of dopaminergic dosage of 2.5mg/ and kg, 5mg/kg and 10 mg/kg, significantly reduced alpha2 and Recently, Chiu et al examined the cognitive effects of the standardized extract Sceletium tortuosum (abbreviated glutamatergic systems. Furthermore, Zembrin® attenuated the @ cholinergic and norepinephrine systems as expected for drugs in Zembrin ) in a RCT study of a cohort of cognitively healthy delta and theta frequency ranges which reflected changes in the typical of analgesic effects of standardized drugs being tested: thetaneurodegenerative wave reduction disorders. in common Zembrin with the induced delta, alpha2the EEG and changes beta1 subjects ( n=21, mean age: 54.6 yrs) administered Zembrin extract, at the daily oral dosage of 25mg, for three weeks [56]. The standardized extract Sceletium tortuosum (Zembrin®) was attenuation. Zembrin® at 10mg/kg markedly attenuated theta manufactured according to European Union Good Manufacturing with the dry plant material: extract ratio of 2:1, standardized Conclusionwaves which reflected and Future the EEG Directions effects of typical antidepressants. topractice a total (GMP).The alkaloid content extract forwas the in thefour form main of Selenium a fine dry alkaloids powder (mesembrenone, mesembrenol, mesembrine and mesembranol) support the potential pivotal High Pressure Liquid Chromatography (HPLC) analysis against andIn serotonin summary, in schizophrenia the findings and from provide the translational the pharmacological studies validatedof 0.4%. The analytical contents ofreference the four alkaloidsstandards were We quantified demonstrated using roles of PDE-4/cAMP/CREB cascade and serotonin in improving the negative symptoms and cognition basis of exploring Zembrin extract via dual targeting both PDE- 4 that Zembrin® treatment compared with the placebo group, selectively and significantly enhanced the cognitive measures of noveldeficits direction in schizophrenia. in regulating The gene paradigm expression of exploring in schizophrenia Zembrin functionexecutive encompasses function (p< higher-order0.032) and cognitive cognitive flexibility processes: (p<0.022) working extract in targeting PDe-4/cAMP/CREB signaling may present a memory,in the computerized attention neurocognitivecontrol, response battery inhibition Vital Signs. and Executive concept on the likelihood of resetting the D-1 activation and NMDA formulation, and is thought to be primarily driven by the prefrontal hypo(Figure function, 2). The and synergy warrant of the serotonin design andof randomized PDE-4 have controlled spinoffs trial of Zembrin extract in the cohort of treatment refractory speed and complex attention. schizophrenia exhibiting persistent negative symptoms and cortex. Zembrin® also improved processing speed, psychomotor

cognitive deficits.

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Figure 2

: Model of PDE-4/cAMP/CREB Cascade in cognition. Bi-directional regulation of cyclicAMP (cAMP) homeostasis is achieved through adenylate cyclase (AD) and phosphodiesterase (PDE) subtype 4. cAMP is activated via either PDE-4 inhibition or hormone/neurotransmitter-stimulated adenyclase cyclase (AD). The cAMP-dependent protein kinase A (PKA), once activated through allosteric site, can phosphorylate cAMP response element binding protein (CREB) to form phosphorylated CREB: pCREB. pCREB associates with transcription co-activator; CREB Binding protein to initiate transcription and translation. model.The CREB-mediated Abbreviations: gene ATP expression (Adenosine contributes triphosphate); towards cAMP long- (Cyclic and Adenosine short-term monophosphate), memory and synaptic Adenylate plasticity. cyclase Zembrin (AC), 5’AMP extract (5’ modulatesadenosine PDE-4 and participates in PDe- 4/cAMP/CREB cascade in cognition. The CREB-linked gene expression has been shown to be impaired in AD

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