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

Abstract

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 Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518.

Figures

Figure 1

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

Figure 2

Cognitive effects of Zembrin extract in healthy subjects: Zembrin-treated subjects and placebo-treated subjects were administered CNS Vital SignR battery of neuropsychological tests at baseline and at the end of the treatment period. Cognitive domains were derived from CNS Vital SignR tests.

Figure 3

PDE-4/cAMP/CREB cascade in cognition: bidirectional 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 adenylate 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 coactivator, CREB binding protein to initiate transcription and translation. The CREB-mediated gene expression contributes towards long- and short-term memory and synaptic plasticity. Zembrin extract modulates 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 model. ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; adenylate cyclase: AC; 5′AMP: 5′ adenosine monophosphate; CREB: cAMP response element binding protein; pCREB: phosphorylated CERB; PKA: phosphokinase A.