Nootropics with potential to (re)build neuroarchitecture

PERSPECTIVE

Nootropics with potential to (re)build neuroarchitecture

Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers. Currently available drugs target symptomatic relief rather than suppressing, ceasing or repairing the devastating neural damages. For Alzheimer’s disease, two classes of procognitive compounds are approved as a treatment. One class is acetylcholinesterase (AChE) inhibitors, including tacrine, donepezil, galantamine and rivastigmine, which increase the acetylcholine neurotransmitter level by inhibiting the hydrolysis of acetylcholine. The other class of drugs is N-methyl-D-aspartate (NMDA) receptor antagonists, including memantine, which are intended to suppress β-amyloid induced excitotoxicity. These compounds have produced only modest improvements in cognitive and behavioral symptoms in some Alzheimer’s disease patients. Thus, tremendous efforts are being made to discover and develop more effective treatments for Alzheimer’s disease.

In the midst of the intense investigation for new treatments, there have been increasing efforts to understand the cellular effects of the existing nootropic compounds on neurogenesis and neuritogenesis, a central process for the formation of neural networks during brain plasticity and (re)growth, to determine their potential for molding neuroarchitecture. Interestingly, studies have shown that selective procognitive compounds indeed possess such properties. We have recently reported that an AChE inhibitor donepezil can significantly promote neurite outgrowth in an embryonic primary cortical culture system (Page et al., 2015). In fact, donepezil can also induce cholinergic sprouting in a rodent model of basocortical degeneration (Ginestet et al., 2007). Interestingly, in addition to its main target, donepezil is known to bind sigma1receptors with high affinity at a low nanomolar range in vitro and behave as an effective sigma1receptor agonist. In fact, sigma1receptor ligands Pre-084 and 4-IBP promote neuritogenesis. Other compounds, including NMDA receptor antagonist memantine and anti-histamine dimebon, which also have been reported to bind sigma1receptors at its effective dose of micromolar range (Peeters et al., 2004), also improve neurite outgrowth (Page et al., 2015). In contrast, non-sigma1-binding compounds, including antioxidants, synaptic vesicle 2A (SV2A) ligands and β-secretase 1 (BACE1) inhibitors, do not exhibit neuritogenic properties when examined under the same experimental conditions. These findings support the notion that sigma1receptors may mediate, in part, the neuritogenic properties of the tested compounds and that sigma1receptors hold a central role in regulating neural plasticity and growth. However, the fact that sigma1receptor compounds are not as potent as the multi-target drug donepezil in our study suggests that more than one molecular target may be ideal in promoting neuritogenesis.

With regard to neuroprotective effects of procognitive compounds, again, donepezil has been reported to enhance the survival of new cells through cAMP response element binding (CREB) signaling. It effectively modulates adult hippocampal neurogenesis and suppresses neurotoxic damage induced by β-amyloid peptide or glutamate exposure (reviewed in Jacobson and Sabbagh, 2008). AChE inhibitors may indeed stimulate neurogenesis as cholinergic receptors are expressed on neuronal progenitors and are coupled to cell proliferation. However, we must take into account that donepezil and other compounds have multiple molecular targets. In fact, similar to the aforementioned neuritogenic property of donepezil, neuroprotective effects of donepezil are thought to be mediated by sigma1receptor interaction in a mouse model (Meunier et al., 2006) and in rodent cortical culture (Marrazzo et al., 2005). For instance, donepezil and sigma1receptor agonist Pre-084 provide a complete neuroprotection while AChE inhibitor tacrine provides only a partial neuroprotection in mice treated with β-amyloid peptide 25-35. Furthermore, the memory-enhancing effect of donepezil is blocked by pre-administration of the sigma1receptor antagonist BD1047 or in vivo antisense probe treatment (Meunier et al., 2006). These studies suggest that the procognitive and neuroprotective activities of donepezil are at least partially mediated by sigma1receptors.

The mechanisms by which sigma1receptors support cellular plasticity and neuroprotection from embryonic stages to adulthood may be many folds. Widely distributed in brain and enriched at focal contacts between mitochondria and endoplasmic reticulum, sigma1receptors form heterodimers with many other membrane receptors. As such, they play a significant neuromodulatory role in common mechanisms for plasticity and neurodegeneration, such as intracellular calcium homeostasis, reactive oxygen specie (ROS) mitigation, mitochondrial function and cholinergic and glutamatergic neurotransmission. Furthermore, several recent studies have indicated the receptor’s role in mitigating reactive astrogliosis in a rodent stroke model and amyotrophic lateral sclerosis (ALS) as well as modulating microgrial activity in animal models of Parkinson’s disease and ALS. In fact, the relevance of sigma1receptors in neuroprotection and repair is evident in several neurodegeneration models. Daily treatment with a sigma1receptor agonist PRE-084 for 5 weeks produces a gradual and significant improvement of spontaneous forelimb use in a 6-OHDA model of Parkinson’s disease. This behavioral recovery is paralleled by an increased density of tyrosine hydroxylase (TH)-positive dopaminergic fibers in striatum and substantia nigra and upregulation of neurotrophic factors BDNF and GDNF. However, PRE-084 has no effect in sigma1receptor knockout animals under the same treatment regime (Francardo et al., 2014). Likewise, PRE-084 or SA4503 attenuates the gradual loss of motor neurons in SOD1G93A mice, a rodent model of ALS (for review, see Ruscher and Wieloch, 2015). In the realm of Alzheimer’s disease, plethora of findings indicate significant role of sigma1receptors in attenuating or reversing the learning impairments or neurotoxicity induced by for example, β-amyloid peptides, ischemia, the cholinergic muscarinic antagonist scopolamine or NMDA receptor antagonist MK-801 in rodents. In some cases, the protective effects of sigma1agonists have been shown to be reversible by antisense oligodeoxynucleotides against sigma1receptors or sigma1antagonists (for review, see Cobos et al., 2008). In support of underlying neuroprotective potential of sigma1receptor activation, amyloid toxin-induced neuronal death can be significantly inhibited by concomitant treatment of PRE-084 or (-)MR-22 with β-amyloid peptides in culture or in vivo (for review, see Ruscher and Wieloch, 2015). Together, these studies show that sigma1receptor activity may antagonize brain pathology of neurodegenerative diseases in preclinical models.

Worthy of mention, there has been a fascinating advancement in the development of a multi-target drug involving sigma1receptor. The aminotetrahydrofuran derivative ANAVEX2-73 is a mixed ligand for sigma1and muscarinic receptors. The compound possesses an anti-amnesic effect when administered shortly before the injection of the muscarinic receptor antagonist scopolamine, NMDA receptor agonist dizocilpine or Aβ25-35oligomers in mice (Villard et al., 2011). In addition, ANAVEX2-73 prevents the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptotic processes in hippocampus of Aβ25-35treated animals (Villard et al., 2011; Lahmy et al., 2015). Intriguingly, administration of ANAVEX 2-73 7 days after Aβ25-35also significantly attenuates learning deficit and lipid peroxidation (T. Maurice and A. Vamvakides, Alzheimer’s Association International Conference® (AAIC) 2012 poster presentation). Moreover, pathological hallmarks of Alzheimer’s disease, Tau hyperphosphorylation and glycogen synthase kinase 3 beta (GSK-3β) activation as well as Aβ1-42seeding induced by Aβ25-35injection, can be mostly blocked by ANAVEX 2-73 treatment in mice (Lahmy et al., 2013). In fact, Anavex Life Sciences Corp. has released a preliminary result of the on-going ANAVEX 2-73 phase 2a clinical trial in both male and female mild-to-moderate Alzheimer’s patients (mostly on donepezil) at AAIC held in Washington, DC this year (S. Macfarlane et al., AAIC 2015 poster presentation). Their preliminary data based on the EEG/ ERP p300 signal, a real-time physiological measure of cognitive processes with demonstrated sensitivity to Alzheimer’s disease pathology, indicates a 38% improvement in the neurophysiological effect in 10 out of 12 patients during part A of the study, which consists of a 36-day on-off-on not-yet-optimized dosing regimen to assess bioavailability. This effect is reported to be consistent with the observed trend in Mini Mental State Examination (MMSE) and Cogstate scale improvements. Taken together, these preclinical studies and the preliminary clinical trial results of ANAVEX 2-73 suggest that sigma1receptors may be a good candidate as a treatment for neurodegenerative diseases indeed. Given the previous clinical failures of selective sigma1receptor ligands to protect against neurodegeneration, it would be of a great interest to see whether a multi-target ANAVEX2-73 could also provide a disease-modifying improvements in the brains of relevant populations of Alzheimer’s disease patients in a long-term. Furthermore, the trial outcome of the combined therapeutic, ANAVEX PLUS, which has shown a synergistic effect of ANAVEX2-73 and donepezil when co-administered with Aβ25-35in mice (Maurice, 2015), would be of a great interest for the field.

To conclude, Alzheimer’s disease is a complex multifactorial pathology, fed by self-amplifying neurodegenerative processes. Monotherapy targeting only a single step of this vicious cycle of degeneration may explain the disappointments in previous clinical trials. Although sigma1receptor presents itself to be a promising candidate, it would be necessary to explore the possibilities of a combinatorial or multi-target therapy, aimed to ameliorate different disease-related mechanisms. As such, it will be crucial also to understand the results of the ongoing and future clinical trials targeting the pathological hallmarks of Alzheimer’s disease, β-amyloid and tau, to investigate whether they could work together to improve the clinical outcomes of the patients with Alzheimer’s disease.

Kyoko Koshibu*

Neuroscience Terapeutic Area, UCB Pharma SA, Braine-l’Alleud, Belgium

*Correspondence to: Kyoko Koshibu, Ph.D., Kyoko.koshibu@ucb.com or Kyoko_koshibu@yahoo.com.

Accepted: 2015-10-15

orcid: 0000-0002-9809-0299 (Kyoko Koshibu)

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10.4103/1673-5374.169635 http∶//www.nrronline.org/

How to cite this article: Koshibu K (2016) Nootropics with potential to (re)build neuroarchitecture. Neural Regen Res 11(1):79-80.