| Autor: |
Nelson TJ; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; West Virginia University, Morgantown, WV, USA., Sun MK; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; West Virginia University, Morgantown, WV, USA., Lim C; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; West Virginia University, Morgantown, WV, USA., Sen A; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; West Virginia University, Morgantown, WV, USA., Khan T; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; West Virginia University, Morgantown, WV, USA., Chirila FV; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; Neurodiagnostics, LLC, Rockville, MD, USA., Alkon DL; Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.; Neurotrope Biosciences, LLC, New York, NY, USA. |
| Abstrakt: |
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD. |
