Phenserine

Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease.[Pubmed:23382994]

PLoS One. 2013;8(1):e54887.

Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid-beta peptide (Abeta) and a loss of trophic factor support. Amelioration of these was assessed with the Abeta lowering AD experimental drugs (+)-Phenserine and (-)-Phenserine in neuronal cultures, and actions in mice were evaluated with (+)-Phenserine. Both experimental drugs together with the metabolite N1-norPhenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of Abeta and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1- and N8-norPhenserine and N1,N8-bisnorPhenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-Phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-Phenserine treatment, in the presence of a (+)-Phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).

Correlations between Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment.[Pubmed:26401704]

J Alzheimers Dis. 2015;47(3):691-704.

New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-beta (Abeta) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Abeta compound Phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Abeta and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with Phenserine, CSF Abeta40 and alpha- and beta-secretase-cleaved soluble amyloid-beta protein precursor (sAbetaPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Abeta40 and sAbetaPP correlated positively with rCMRglc and cognition while CSF Abeta42 levels, the Abeta42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term Phenserine treatment resulted in increased levels of CSF Abeta40, sAbetaPPalpha, and sAbetaPPbeta, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.

(-)-Phenserine attenuates soman-induced neuropathology.[Pubmed:24955574]

PLoS One. 2014 Jun 23;9(6):e99818.

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-Phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-Phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-Phenserine warrants further evaluation as an OP nerve agent protective strategy.

Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms.[Pubmed:27254111]

PLoS One. 2016 Jun 2;11(6):e0156493.

Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound Phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of Phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with Phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with Phenserine effectively reversed injury-induced regulations in the 'Blalock Alzheimer's Disease Up' pathway. Together these data suggest that multiple Phenserine-associated actions underpin this compound's ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI.

Phenserine.[Pubmed:17594192]

Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97.

Phenserine, a derivative of physostigmine, was first described as an inhibitor of acetylcholinesterase (AChE) and was shown to improve cognition in various experimental paradigms in rodents and dogs. It was clinically tested for Alzheimer's disease, with moderate success in initial Phase II studies. Phenserine deserves attention for an additional quality of action: in addition to inhibiting AChE, it modulates the amount of beta-amyloid precursor protein (APP) in neuronal cell culture by reducing APP translation. This effect probably involves interaction of Phenserine with a regulatory element in the 5'-untranslated region of the APP gene that controls APP expression. Phenserine apparently reduces translational efficiency of APP mRNA into protein, a process that may involve an interaction with iron and/or an iron-responsive element. As a consequence, Phenserine reduces beta-amyloid peptide (Abeta) formation in vitro and in vivo. Phenserine is also unique because of differing actions of its enantiomers: (-)-Phenserine is the active enantiomer for inhibition of AChE, whereas (+)-Phenserine ('posiphen') has weak activity as an AChE inhibitor and can be dosed much higher. Both enantiomers are equipotent in downregulating APP expression. (+)-Posiphen may be a promising drug, either alone or in combination with (-)-Phenserine, to attenuate the progression of Alzheimer's disease.

Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-beta peptide.[Pubmed:16690718]

J Pharmacol Exp Ther. 2006 Aug;318(2):855-62.

A wealth of independent research with transgenic mice, antibodies, and vaccines has pointed to a causative role of the amyloid-beta peptide (A beta) in Alzheimer's disease (AD). Based on these and earlier associative studies, A beta represents a promising target for development of therapeutics focused on AD disease progression. Interestingly, a cholinesterase inhibitor currently in clinical trials, Phenserine, has been shown to inhibit production of both amyloid precursor protein (APP) and A beta. We have shown that this inhibition occurs at the post-transcriptional level with a specific blocking of the synthesis of APP relative to total protein synthesis (Shaw et al., 2001). However, the dose of Phenserine necessary to block APP production is far higher than that needed to elicit its anticholinesterase activity, and it is these latter actions that are dose limiting in vivo. The focus of this study was to screen 144 analogs of Phenserine to identify additional small molecules that inhibit APP protein synthesis, and thereby A beta production, without possessing potent acetylcholinesterase (AChE) inhibitory activity. An enzyme-linked immunosorbent assay was used to identify analogs capable of suppressing APP production following treatment of human neuroblastoma cells with 20 muM of compound. Eight analogs were capable of dose dependently reducing APP and A beta production without causing cell toxicity in further studies. Several of these analogs had little to no AChE activities. Translation of APP and A beta actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics.

The cholinesterase inhibitor, phenserine, improves Morris water maze performance of scopolamine-treated rats.[Pubmed:15620572]

Life Sci. 2005 Jan 21;76(10):1073-81.

Male Fischer-344 rats (n = 38) at 5 months old were tested in a Morris water maze to determine if treatment with the cholinesterase inhibitor, Phenserine (PHEN), would overcome a learning impairment induced by scopolamine (SCOP), a muscarinic cholinergic receptor antagonist. Each rat was randomly assigned to one of five groups to receive two intraperitoneal injections 60 and 30 min, prior to testing, respectively, as follows: (1) saline-saline (SAL); (2) saline-1.0 mg/kg (SCOP); (3) 2 mg/kg PHEN- SCOP (PHEN2); (4) 4 mg/kg PHEN-SCOP (PHEN4); and (5) 1 mg/kg PHEN-SAL (PHEN1). Maze testing occurred across 5 days with 4 days of acquisition trials (4 trials per day) and a fifth day consisting of a single 120 sec probe trial. PHEN1 and SAL were combined into one control (CON) group for purposes of statistical analysis for both acquisition and probe trials as comparison of the two groups revealed that they did not significantly differ on any measure. SCOP-treated rats were significantly impaired compared to CON in learning the location of the submerged platform as measured by latency to locate the platform and the distance traversed to find the platform across days of testing. The PHEN4 group had significantly lower latencies and traveled a shorter distance to reach the submerged platform when compared to SCOP on the fourth day of trials while the PHEN2 group traveled more directly to the submerged platform but did not have shorter latencies than the SCOP group. For probe trials, CON rats swam closer to the target area (a measure of proximity to the removed platform) than did all other groups, and the PHEN4 group swam in an area more proximate to the target area than did the SCOP-treated group. These findings demonstrate the ability of this drug to improve learning when cholinergic function has been impaired in a spatial memory task.

Phenserine ((-)-Eseroline phenylcarbamate) is a derivative of Physostigmine and is a potent, noncompetitive, long-acting and selective AChE inhibitor. Phenserine reduces β-amyloid precursor protein (APP) and β-amyloid peptide (Aβ) formation. Phenserine improves cognitive performance and attenuates the progression of Alzheimer's disease.

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