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

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 Pr