Safety Study of the Effect of Scelectium Tortuosum (as Zembrin®)in Aged Normals

Overview

Phosphodiesterase is a candidate for the Rx \& prevention of cognitive and psychotic disorders. Since caffeine targets primarily PDE4(Phosphodiesterase subtype 4), caffeine analogs have been developed to mimic the actions of caffeine's ability to inhibit PDE-a, PDE4, PDE5 and adenosine-2 (AD-2)but are limited by the side effects of insomnia and heightened anxiety. Sildenafil (PDE-5 inhibitor) fails to enhance cognition in schizophrenia. The study of PDE-4 in cognition in Alzheimer's dementia and schizophrenia has been done using the PDE-4 prototypal compound, rolipram, which improves cognition in rodents. Rolipram reverses the memory deficits induced by amyloid fragment Abeta25-35 and Abeta1-40 peptide. In humans the frequent side effect of vomiting hampers translational research. The clinical trial of rolipram in multiple sclerosis was terminated prematurely due to serious adverse events with paradoxical increases in MRI MS-specific brain lesions. However, PDE-4 remains paradigm for cognition. Another strategy is chemical moieties capable of antagonizing the PDE-4 through allosteric modulation, rather than direct competitive inhibition hoping to minimize adverse events while retaining the biological potencies and functional responses of PDE-4 Modulators. Dietary supplements with PDE-4 effects have advantages in that small investments are needed to adequately study them. Pharmacologically active chemicals of Sceletium species are mesembrine-type alkaloids that have proven PDE-4 activity. The PDE-4D knockout mice have enhanced memory function mediated through hippocampal neurogenesis via phosphorylated cAMP response element binding protein (pCREB) signaling. This study purpose is to delineate the relationship of PDE-4 and cognition in normals. pCREB is possibly the putative biomarker of PDE-4 response with CREB as effector signaling pathway of PDE-4. CREB is close to nuclear receptors represented by BDNF (Brain Derived Neurotrophic Factor) and PPAR (Peroxisome Proliferator Activating Receptor) complexes. CREB changes in neuronal plasticity are targets for pharmacological paradigms for cognitive enhancement. This study will use the scelectium tortuosum as manufactured as Zembrin®. The findings in control subjects will form the basis for designing future studies of Zembrin® in neurodegenerative disorders with marked cognitive impairment such as Alzheimer's Dementia and Parkinson's Disease.

1\. Contextual Background For the past decade, converging evidence suggests that targeting PD Phosphodiesterase for cognition represents novel heuristic approaches for development of dietary supplements and drug candidates for the treatment and prevention of cognitive and psychotic disorders. 1. . The earlier findings on caffeine as the prototypal PD inhibitor targeting primarily PDE4 (Phosphodiesterase subtype 4) has stimulated synthesis of caffeine analogs to improve upon the pharmacokinetic profile and benefits/risk ratio. 2. . The dual actions of caffeine as inhibitor of PDE-a, PDE4 and PDE5 and adenosine-2 (AD-2) antagonist, exerts multiple brain-behavior functions including sleep, cognition, memory and learning. It remains to be seen whether caffeine analogues live up the therapeutic potential in neurodegenerative diseases while bypassing the side effects of insomnia and heightened anxiety. Sildenafil (Viagra R) PDE-5 inhibitor indicated for erectile dysfunction (ED) fails to enhance cognition in schizophrenia 3. . The full dosage range may not have been explored in the study with sildenafil. It is noteworthy that PDE-5 inhibition is related to NMDA (N-methyl-d-aspartic acid) glutamatergic modulation. In conducting a Pub Med search of recent studies point to the role of PDE-4 in diverse domains of cognition: memory, attention, executive function, recall, visual-spatial tasks. We find converging evidence targeting PDE-4 as the novel approach towards treating the cognitive deficits in Alzheimer dementia and schizophrenia 4. . Most of the preclinical studies focus exclusively on the PDE-4 prototypal compound, rolipram. Rolipram improves memory consolidation, working memory and information processing in rodent species subjected to a variety of cognitive tasks: radial arm maze, passive avoidance, delayed arm water maze 5. . A very recent study found that rolipram, reverses deficits induced by amyloid fragment Abeta25-35 and Abeta1-40 peptide in the Morris water maze and passive avoidance task 6. . In preclinical screening of PDE-4 inhibitors, vomiting mediated via activating the area postema has been consistently noted. Tolerability and safety has hampered significantly the translation research in PDE-4 inhibitors. The clinical trial of rolipram in multiple sclerosis was terminated prematurely due to serious adverse events with paradoxical increases in MS-specific brain lesions identified by MRI 7. . Notwithstanding the challenges in translational research, the molecular template of PDE-4 remains a highly viable paradigm for cognition. Drug Design has adopted another strategy in developing chemical moieties capable of antagonizing the PDE-4 pharmacological effects. Through allosteric modulation, rather than direct competitive inhibition at the catalytic site domain of PDE-4, the hope is to minimize the adverse events while retaining the biological potencies and functional responses relevant to the pharmacological activities of PDE-4 compounds. 8. . The emergence of PDE-4 Modulators (PDE-4M) has attracted attention. Dietary supplements possessing the molecular templates and requirements in PDE-4 design strategy have added advantages in that preliminary clinical studies can be undertaken with a disproportionately small investment. If the preliminary results are favorable, strategic advances to GMP patented drug candidates are more predictable and confer less fiscal and clinical risks without compromising the efficacy stipulation in satisfying FDA criteria for phase II and Phase III trials. Our study the Zembrin® formulation of Scelectium Toruosum in cognition expands on an earlier study protocol which investigated the effects of Zembrin® in Generalized Anxiety Disorder (GAD). The pharmacologically active chemicals from the Sceletium species belong to mesembrine-type alkaloids; the structures are well characterized. Structure-activity relationship of the mesembrine-derivative alkaloids has been delineated in in-vitro assay of recombinant PDE-4 regarding the relative potencies in producing the functional responses. The IC50 of mesembrine-HCL is determined to be 20 microM 9. . The PDE-4D knockout mice model provides evidence of enhanced memory function is mediated through hippocampal neurogenesis via phosphorylated cAMP response element binding protein (pCREB) signaling. 10. . Microinfusion of lentiviral vectors carrying micro RNAs targeting the long-form of PDE4D isoforms directly into bilateral dentate gyrus of the hippocampus in the mice resulted in improved performance scores in object recognition test, water maze and radial arm maze. These considerations lead us to organize a pilot "proof-of-concept study" to delineate the relationship of PDE-4 and cognition in normal control subjects to validate the target of PDE-4 in modulating cognition functions in normal control subjects. It is noteworthy that none of the preliminary studies include measure of cAMP signaling in clinical subjects to correlate with brain-behavior interactions. With the availability of sensitive, reliable and valid ELISA method of assaying for pCREB, we consider it important to examine pCREB as the putative biomarker of PDE-4 response in clinical subjects treated with Zembrin®. There is emerging an increase of evidence in support of the construct that CREB as the effector signaling pathway of PDE-4, is the target of diverse classes of antidepressants 11. . CREB is the late molecular partner to the family of nuclear receptors represented by BDNF (Brain derived neurotrophic factor) and PPAR (Peroxisome Proliferator Activating Receptor) complex 12. . CREB reflects changes in neuronal plasticity and is sensitive to pharmacological paradigms for cognitive enhancement. CREB signaling integrates signal transduction from related neurotransmitters and neuromodulators besides PDE-4. Neuronal alpha-7 nicotinic receptor agonist A-582941 exerts its cognitive effects through interacting with phosphorylation of CREB pathway (13). The findings in control subjects will form the rational basis for designing controlled studies of Zembrin® in neurodegenerative disorders with marked cognitive impairment such as Alzheimer's Dementia and Parkinson's Disease.