Mariwan Husni

Liposomal-formulated curcumin [Lipocurc™] targeting HDAC (Histone Deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson’s disease: implications for epigenetics-based nanotechnology-driven drug platform

Abstract Background: Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson’s disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain. Methods: In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem. Results: We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025). Conclusions: We demonstrated for the first time Lipocurc™’s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

The Role of Nutrient-Based Epigenetic Changes in Buffering Against Stress, Aging, and Alzheimer’s Disease

Converging evidence identifies stress-related disorders as putative risk factors for Alzheimer Disease (AD). This article reviews evidence on the complex interplay of stress, aging, and genes-epigenetics interactions. The recent classification of AD into preclinical, mild cognitive impairment, and AD offers a window for intervention to prevent, delay, or modify the course of AD. Evidence in support of the cognitive effects of epigenetics-diet, and nutraceuticals is reviewed. A proactive epigenetics diet and nutraceuticals program holds promise as potential buffer against the negative impact of aging and stress responses on cognition, and can optimize vascular, metabolic, and brain health in the community.

Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer’s Dementia

Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were found. Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimers dementia. This trial is registered with ClinicalTrials.gov NCT01805518.

Kurdish Refugees’ View of Politically Motivated Self-Immolation

Self-immolation has been used as a political tool by various oppressed groups, including Kurdish refugees. To examine sociodemographic correlates of the views on self-immolation, we carried out semi-structured interviews with 54 Kurdish refugees (18 women, 36 men). The majority of these refugees (74.1%) indicated that they did not expect self-immolations to help in obtaining freedom for Kurdistan. Their opinions on this issue were uniform across educational and occupational levels, gender, number of years since escape, and other socio-demographic variables, except age. Younger refugees were less likely to see self-immolation as politically effective. The belief in self-immolation was uncorrelated with the frequency of post-traumatic nightmares dealing with the escape from or persecution in Kurdistan.

Exploratory study of sublimed sulfur, in cognitively normal subjects and in Alzheimer’s dementia (AD) subjects: implications for Sulfur targeting Hydrogen sulfide (H2S)/Homocysteine (Hcy) and beta-galactosidase (GALAC)/Autophagy Signaling in AD

Introduction: There is mounting evidence to suggest that hyper-homocysteinemia (eHct) correlates with cognitive decline severity and cortical atrophy in AD. Hydrogen Sulfide (H2S) exerts neuroprotection through regulating Homocysteine (eHcy) signaling. Elemental sulfur can mediate H2S neuroprotection through the trans-sulfuration pathway and correct the the dysregulation of H2S /Hct signaling in AD. Sublimed Sulfur, formulated as SULMEDOL and approved for the treatment of lactose intolerance, activates gut beta-galactosidase (GALAC). We repurpose Sulmedol from lactose intolerance to likely CNS effect, since gut GALAC crosstalks with senescence-related GALAC expression in the brain. In view of the known regulatory function of GALAC in CNS endosomal-lysosomal autophagy system , we propose that SULMEDOL may rescue aberrant autophagy in AD. Methods: We hypothesize that sublimed Sulfur (SS), via targeting H2S/Hcy and GALAC, may be efficacious in AD. In study I, we examined the 30-day treatment effects of SS at daily dosage of 200 mg to be administered at in altering the plasma Hcy levels in a small cohort of cognitive normal subjects. We stratified the cohort of cognitively normal control subjects to be administered SS into three groups with pre-determined range of basal fHCy levels as follows: Group 1 (n=16): range of fHcy 10.0-22.1 μmol/L; Group 2(n=15) fHcy range:7.1-9.9 μmol/L;Group 3 (n=15); range of fHcy 2.3-7.0 μmol/L . Primary outcome was defined as change in Hcy from baseline to 24-hr and 30-day post-treatment period. In study II, we evaluated the safety and tolerability of SS in two AD patients were treated with 200 mg for 3 months, with Clinical Global Impression–Global Improvement (CGI –I) scale as the primary outcome measure. Results: In Study I, Group I subjects, fHcy decreased significantly by 36.1%, 24 hours after treatment and by 29.3%, 30 days later.In Group 2 fHcy did not change significantly. Group 3 exhibited paradoxical non-significant increase in fHcy, without change in erythrocyte folic acid, serum lipids and vitamin B12. SS was well tolerated in all patients. In Study II, clinical vignette analysis of two AD patients revealed that 3-month SS treatment ameliorated cluster of AD symptoms: nocturnal wandering, paranoid delusions, disorientation and confusion. CGI-I scale score was “very much improved”. No serious adverse events were reported. Conclusions: SS in dual targeting H2S-homocysteine inflammation signaling and GALAC autophagy pathway related to AD, holds promise in therapeutic development of AD. Our findings warrant controlled trial of SS in AD. Correspondence to: Lawson Health Research Institute, London Ontario; University Western Ontario, London, ON, Canada; Parkwood Mental Health Institute, St Joseph Health Care, London ON, Canada, E-mail: schiu3207@ rogers.com

Exploring Zembrin Extract Derived from South African Plant, Sceletium tortuosum in Targeting cAMP-driven Phosphodiesterase (PDE) Signaling in Alzheimer’s Disease: Synthesis of Evidence

Recently with the changing landscape of the aging population and the increase in incidence of Alzheimer’s disease (AD), there has been marked interest to develop strategies to prevent, delay and modify AD. We review the diverse lines of evidence in support of the emerging role of cAMP-mediated Phosphodiesterase (PDE) signalling with respect to aging, inflammation and depression. In view of the link of PDE to Epigenetic complex, targeting PDE through designing modulators and inhibitors of PDE may represent a novel approach in AD therapeutics. We review critically the translational studies of the proprietary Zembrin extract harvested and processed from the South African plant, Sceletium tortuosum, highlighting the dual property of Zembrin in targeting coupling of PDE and serotonin signaling mechanisms in vitro and in vivo models of AD and cognition. The promising clinical findings of Zembrin in cognition suggest that Zembrin extract may merit randomized controlled trials in AD to establish the efficacy and safety in AD.