Posts Tagged ‘Motoki Takagi’

Reporter: Aviva Lev-Ari, PhD, RN

Featured Researcher:

Prof. Beth Murinson, MD, PhD   of Technion’s Rappaport Faculty of Medicine came to Technion after being a professor at Johns Hopkins Medical School. She discusses her research in the field of Neurology and pain management.

Prof. Beth Murinson, MD, PhD, at Technion’s Rappaport Faculty of Medicine, has been a very busy person since coming to Israel in 2010 with her husband and two children. Before Technion she was an associate professor at Johns Hopkins Medical School. A neurologist who specializes in injury to the peripheral nerve, these days Murinson can be found in her laboratory and at Rambam hospital. She conducts research and works on educational projects that are designed to treat patients with acute and persistent pain; teaches medical students, both the Israeli students and those from the USA who are in TeAMS – Technion’s American medical school program; advises medical students in the USA; is an attending neurologist in the Department of Neurology at Rambam Health Care Campus and runs an outpatient clinic specializing in peripheral nerve injuries, chronic neuropathic pain and back injuries.

Murinson’s research is focused on chemotoxic and traumatic injuries to the nerve. Her two main research models address the response of growing peripheral nerve cells to exposure to a common pharmacological agent and deal with nerve injury. She is trying to determine what is the least amount of injury that will produce neuropathic pain; it is important to understand what injuries are painful and which injuries are not. Her goal is to find methodology or treatments that will help prevent induced nerve injury. There are some drugs that are widely used and taken by millions of people that have the potential to harm nerves. She also works in collaboration with the oncology group at Rambam.



“To find methodology or treatments that will help prevent induced nerve injury.”

Murinson’s academic credentials are impressive; she got an early start by graduating high school early and proceeding to receive her Bachelor’s degree in mathematics from Johns Hopkins, a Master’s from UCLA in biomathematics, and an MD/Phd (in physiology) from the University of Maryland, graduating with honors. After, she did her residency in neurology at Yale and she finished her education with a fellowship in neuroelectrophysiology back at Johns Hopkins.

It’s a wonder she found time to write a book.

Take Back Your Back is the volume to read if you are suffering from back pain. The book lets patients know everything they can do to regain control over their lives after a back injury. It provides a wealth of information on what can go wrong with the back and how patients can take charge of their own recovery.



Flaviogeranin, a new neuroprotective compound from Streptomyces sp.

Yoichi Hayakawa, Yumi Yamazaki, Maki Kurita, Takashi Kawasaki, Motoki Takagi and Kazuo Shin-ya


Cerebral ischemic disorders are one of the main causes of death. In brain ischemia, blood flow disruptions limit the supply of oxygen and glucose to neurons, initiating excitotoxic events.

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
The Journal of Antibiotics 63, 379-380 (July 2010) | doi:10.1038/ja.2010.49

Sarcophytolide: a new neuroprotective compound from the soft coral Sarcophyton glaucum.

F A BadriaA N GuirguisS PerovicR SteffenW E MüllerH C Schröder

Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Egypt.
Toxicology (impact factor: 3.68). 12/1998; 131(2-3):133-43.
Bioactivity-guided fractionation of an alcohol extract of the soft coral Sarcophyton glaucum collected from the intertidal areas and the fringing coral reefs near Hurghada, Red Sea, Egypt resulted in the isolation of a new lactone cembrane diterpene, sarcophytolide. The structure of this compound was deduced from its spectroscopic data and by comparison of the spectral data with those of known closely related cembrane-type compounds. In antimicrobial assays, the isolated compound exhibited a good activity towards Staphylococcus aureus, Pseudomonas aeruginosa, and Saccharomyces cerevisiae. Sarcophytolide was found to display a strong cytoprotective effect against glutamate-induced neurotoxicity in primary cortical cells from rat embryos. Preincubation of the neurons with 1 or 10 microg/ml of sarcophytolide resulted in a significant increase of the percentage of viable cells from 33 +/- 4% (treatment of the cells with glutamate only) to 44 +/- 4 and 92 +/- 6%, respectively. Administration of sarcophytolide during the post-incubation period following glutamate treatment did not prevent neuronal cell death. Pretreatment of the cells with sarcophytolide for 30 min significantly suppressed the glutamate-caused increase in the intracellular Ca2+ level ([Ca2+]i). Evidence is presented that the neuroprotective effect of sarcophytolide against glutamate may be partially due to an increased expression of the proto-oncogene bcl-2. The coral secondary metabolite, sarcophytolide, might be of interest as a potential drug for treatment of neurodegenerative disorders.

Pharmacological treatment of Alzheimer disease: From psychotropic drugs and cholinesterase inhibitors to pharmacogenomics

Cacabelos, R., et al.

Drugs Today 2000, 36(7): 415
ISSN 1699-3993
Copyright 2000 Prous Science
CCC: 1699-3993

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more “molecular approach” based on new data on the pathogenic events underlying neurodegeneration in AD.

In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into 4 main categories:

  • primary events (genetic factors, neuronal apoptosis),
  • secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss),
  • tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and
  • quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction).

All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis.

This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment.

  • Stem-cell activation,
  • genetically manipulated cell transplantation,
  • gene therapy and
  • antisense oligonucleotide technology

constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration.

The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.



Dementia is a major problem of health in developed countries. Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50–70% of the cases, followed by vascular dementia (30–40%) and mixed dementia (15–20%). Approximately 10–15% of direct costs in dementia are attributed to pharmacological treatment, and only 10–20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype–phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20–95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.

Key words  dementia – Alzheimer’s disease – APOE – CYP2D6 – pharmacogenetics – pharmacogenomics – multifactorial treatments


Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Edward C. Lauterbach; Jeff Victoroff; Kerry L. Coburn; Samuel D. Shillcutt; Suzanne M. Doonan; Mario F. Mendez


This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer’s and Parkinson’s diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

The most important detailed findings for each drug are briefly summarized in Table 1, Table 2, Table 3, and Table 4 (located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI). The recently discovered TDP-43 was also considered while this project was underway, but no relevant articles were evident for this protein.

It is evident from the above that there is significant variation in degree of investigation, cell lines studied, and methodological approaches. Other limitations include the varying use of neural tissues, variance in the neuronal types studied, use of neuroblastoma lines instead of neurons, study of immature or poorly differentiated cells that may be more prone to apoptosis than more mature cells, and the infrequent characterization of effects on αSyn, tau, and Aβ. Such deficiencies in the data significantly confound the ability to draw definitive conclusions. In particular, the deficiencies in the data raise the question as to the most valid, clinically relevant, and appropriate standards of evidence to apply in determining which preclinical findings will predictably translate into clinical neuroprotection in patients with neurodegenerative diseases.

A number of concerns impact the selection of an appropriate standard of evidence. First, there are no established general criteria for judging preclinical neuroprotective data across the diversity of neurodegenerative diseases. Second, unlike clinical evidence-based medicine (EBM) standards, there do not appear to be established uniform criteria for judging the diversity of preclinical findings. From an EBM perspective, the data considered here are even less compelling than Class II or IV18 or Level C19clinical case reports since they generally do not pertain to findings in human patients. Third, there are considerable variabilities across the present preclinical findings with respect to intra- and extramodel replication, replications in neural tissue, the specific neural tissues studied, and the specific brain locus even when neurons are consistently studied. These are summarized in Table 5. Fourth, replications are still needed using the same physiological dose range, particularly because some have observed bell—shaped rather than sigmoid—shaped neuroprotective dose—response curves.20,21 Fifth, some drugs have mixed actions, simultaneously possessing some neuroprotective actions and other neurodegenerative actions. It is not yet clear whether the various actions should receive equal weight or whether one may trump others (for example, effects on apoptotic measures may be more determinative in importance than effects on more “upstream” processes such as mitochondrial potential or proteasomal function). Sixth, there is no gold-standard preclinical model but, instead, a diversity of models that each have their own select benefits and limitations. These and other factors likely contribute to the current disconnect between preclinical findings and neuroprotective clinical trial results.

Some criteria for considering neuroprotective candidate agents have been elaborated in Parkinson’s disease22 and stroke.23 In Parkinson’s disease, scientific rationale, penetration of the blood-brain barrier, safety and tolerability, and efficacy in relevant animal models of the disease or an indication of benefit in human clinical studies constitute criteria.22 In the case of FDA-approved psychotropics reviewed here, which essentially meet most of these criteria (with the exception of systematic, consistent application in relevant neurodegenerative disease models), the question then becomes: how good is the available preclinical evidence of neuroprotection? Ravina et al.22 noted that the most problematic issue in Parkinson’s disease was evaluating animal data given the many different models that were of uncertain value in predicting results in humans and noted further that a clinical trial would actually be needed to demonstrate the predictive validity of any preclinical model. Similarly, it is not possible to judge the quality of the present preclinical findings by the models used because the predictive validities of the models remain unclear. In stroke,23 potentially successful drug candidates have been considered to be inferable from preclinical data by the following criteria: (a) adequately defined dose-response relations; (b) time window studies showing a benefit period; (c) adequate physiological monitoring in unbiased, replicated, randomized, blinded animal studies; (d) lesion volume and functional outcome measures determined acutely and at longer term followup; (e) demonstration in two animal species; (f) submission of findings to a peer-reviewed journal. However, even with these criteria, Gladstone et al.24 have pointed out that translation of preclinical findings to clinical efficacy has been hampered by a lack of functional outcomes, long-term end points, permanent ischemia models, extended time windows, and selective white matter evaluation in preclinical models whereas clinical studies are plagued by insensitive outcome measures, lack of stroke subtype specificity, and inattention to the ischemic penumbra, among other concerns. Ford25 has also pointed out that a number of compounds fulfilling these stroke neuroprotectant criteria have failed to afford translational clinical neuroprotection. Analogous concerns obtain for neurodegenerative disease preclinical models and clinical methods, particularly whether putative criteria will reliably predict translation to clinical neuroprotection. Additionally, a nearly endless array of clinical variables including gender, age, pharmacogenomics, medical history, coadministered drugs, and other factors may contribute to an inability to predict clinical neuroprotection despite preclinical success. Thus, predictive criteria remain in need of development.

Reflection upon these translational issues in regard to psychotropic neuroprotection in neurodegenerative diseases first suggests the need for replication within and between specific preclinical models in specific neurons at specific loci to elucidate physiological dose-response relations that should then themselves be replicated as a first step. Additionally, other issues seem relevant to the problem of determining which candidate drugs may be most likely to effect clinical neuroprotection. We suggest preliminary neuroprotective drug selection criteria for assessing the likelihood of translational clinical neuroprotection in neurodegenerative diseases (Table 6). These criteria, including preclinical (at least two replicated neuroprotective actions at physiological doses in an established neuroprotective model, neural tissue, and disease-specific animal model in excess of the number of known neurodegenerative actions) and clinical (delayed progression on clinical markers and unexpected benign disease course not accounted for by symptomatic properties) criteria, can be evaluated over time and modified as future data indicate. Given the lack of information regarding the utility of specific preclinical paradigms in predicting clinical neuroprotective effects, it is premature to rank or weight these criteria. Rather, recent concerns26 notwithstanding and until a better study methodology is developed, we suspect that the greater the number of criteria met by a candidate drug, the greater the likelihood of demonstrating translational clinical neuroprotective efficacy in a randomized, double-blind, placebo-controlled, delayed-start or randomized-withdrawal clinical trial.27 Such trials are needed because agents deemed promising based upon preclinical data often fail to demonstrate neuroprotection in clinical trials for reasons identified in the above paragraph. At present, preclinical demonstration of replicable neuroprotective effects in neural tissues at clinically-relevant doses does not assure a positive result in a clinical trial, nor does the absence of such evidence necessarily exclude clinical neuroprotective benefits. Until such clinical findings obtain, it is impossible to identify preclinical determinants predictive of translational clinical success and ascertain whether patients are actually being helped or harmed in a neuroprotective sense by the use of these drugs.

Beyond the methodological concerns expressed above, a practical assessment of these preclinical findings is still possible. Given the relative infancy of this field of research, the present state of the literature, the limitations of the data described above, and our current ignorance of preclinical evidence predictive of successful clinical translation, there is the very real possibility of prematurely disregarding findings that may ultimately prove to be of clinical significance with further research (a “type II” error) by applying an overly stringent standard of evidence. It seems that, at the present time, the proper approach is to instead look at the preponderance of the available findings and attempt some generalizations that constitute general impressions to be tested in future research, similar to the process of developing and refining clinical diagnostic criteria. Accordingly, the following observations are drawn from looking at all of the studies, without any exclusions, except where there are clearly contradictory data. As noted, many of the findings have not yet been independently replicated in the same model despite apparent replication in a different model (Table 5). Until the state of the literature develops to the point where independent replications in the same model are routinely observed, appropriate assessment criteria must be very liberal, resulting in conclusions that can only be viewed as preliminary. Adopting this approach with its attending caveats, some preliminary observations can be gleaned from the data. Below, we first consider drugs with respect to their neuroprotective potentials, distinguishing drugs meriting further study from those that have limitations dissuading further investigation and those for which too little data are available to form any conclusions. (We also summarize neuroprotective effects by drug class in Appendix 1 and drugs by neuroprotective actions in Appendix 2 [located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI%5D; Part 2 of this report focuses on the broader neuroprotective aspects of selected psychopharmacological classes.) Next, we assess the general properties of the various classes of psychotropics. We then consider each investigated cellular function with regard to the drugs that influence them. Finally, we detail a research agenda for drugs of interest and consider the progress made in clinical neuroprotective trials thus far, recommending a next step in their development.

Drugs of Neuroprotective Interest

Drugs meriting further study include:

  • pramipexole,
  • thioridazine,
  • risperidone,
  • olanzapine,
  • quetiapine,
  • lithium,
  • valproate,
  • nortriptyline,
  • desipramine,
  • maprotiline,
  • fluoxetine,
  • paroxetine,
  • buspirone,
  • clonazepam,
  • diphenhydramine, and
  • melatonin.

These are drugs with at least one significant neuroprotective action and relatively negligible countervailing neurodegeneration—promoting effects, as summarized in Table 1, Table 2, and Table 3 (especially the “Comments” column summarizing the data), and particularly Table 7 (tables located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI).

Drugs that are not recommended for further study at the present time due to more significant limiting issues (see Table 1, Table 2, and Table 3, especially “Comments” column summarizing the data). Haloperidol does not warrant further study because of tau hyperphosphorylation, reduced cell viability, and multiple proapoptotic actions, especially in hippocampus, cortex, striatum, and nigra. Fluphenazine, chlorpromazine, and clozapine, probably do not warrant further study because of multiple proapoptotic actions, and chlorpromazine inhibits tau dephosphorylation. Carbamazepine has variable neuroprotective properties. Oxcarbazepine promotes apoptosis. Clomipramine also generally promotes apoptosis. Diazepam has mixed effects on neural apoptosis, but uncouples oxidative phosphorylation, releases cytochrome c, and promotes apoptosis in a number of neuronal models, although it promoted ATP recovery and prevented cytochrome c release in a single study of ischemic hippocampal slices.

It should be emphasized that there are no convincing clinical data at present to indicate that these drugs are unsafe for clinical use due to neurodegenerative effects, only preclinical evidence to temper enthusiasm for clinical trial application as a neuroprotectant. Until such data become available, the use of these drugs continues to be guided by clinical symptomatic indications. The limiting actions described above are considered to be significant enough to likely detract from an overall neuroprotective effect, making positive findings less likely, hence our inability to recommend them at present. It must also be recognized that some of these limitations still await replication (Table 5), and that it is presently unknown precisely which neuroprotective modes of action are positively and negatively predictive of clinical neuroprotection.

Drugs for Which Limited Data Do Not Allow Recommendations

There are currently insufficient data for ropinirole, amantadine, thiothixene, aripiprazole, ziprasidone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, bupropion, sertraline, fluvoxamine, citalopram, trazodone, nefazodone, venlafaxine, duloxetine, mirtazapine, chlordiazepoxide, flurazepam, temazepam, chlorazepate, lorazepam, oxazepam, alprazolam, zolpidem, cyproheptadine, hydroxyzine, modafinil, ramelteon, benztropine, trihexyphenidyl, and biperiden.

Briefly, regarding the neuroprotective effects of psychopharmacological classes, certain generalizations are apparent (see Appendix 1 for details). There is some evidence to suggest that D2 agonists, lithium, some SSRIs, and melatonin reduce . D2 agonists, certain atypical antipsychotics and antidepressants, and melatonin suppress . Neuroleptics, lithium, certain heterocyclic antidepressants, the central benzodiazepine receptor agonist clonazepam, and melatonin inhibit . D2 agonists, atypical antipsychotics, lithium, antidepressants, the 5HT1a agonist buspirone, and melatonin inhibit , whereas the peripheral benzodiazepine receptor agonist diazepam promotes apoptosis. These, however, are gross generalizations, which are better explained in Appendix 1 and Appendix 2. Moreover, it is potentially erroneous to project neuroprotective effects upon a pharmacological class because neuroprotective properties may not relate to their currently recognized pharmacodynamic effects.

Above, we have indicated which drugs merit further study, those which cannot be recommended due to significant limiting issues, and those with inadequate data to allow assessment. Among drugs meriting further study, Table 8 discloses the various agents along with evidential weights for their various neuroprotective actions. It can be seen that drugs that inhibit apoptosis and have at least one other general antiapoptotic action (each demonstrated by a net of two or more studies supporting a neuroprotective action, without consideration of their effects on specific proteins) include pramipexole, olanzapine, lithium, desipramine, and melatonin. The remaining agents have less robust findings supporting general neuroprotective actions. Considering the effects of these drugs on proteins and at least one other neuroprotective action in a disease-specific model, the most promising drugs in Alzheimer’s disease would include olanzapine, lithium, and melatonin while drugs with less robust support in Alzheimer’s disease include pramipexole, quetiapine, valproate, and desipramine. Applying the same criteria, drugs of promise in Parkinson’s disease include pramipexole and melatonin, while drugs with less robust support in Parkinson’s disease include olanzapine, lithium, valproate, desipramine and clonazepam. Similarly, in Huntington’s disease, desipramine is the most promising, with less robust support for lithium, valproate, nortriptyline, and maprotiline. There is some support for pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis. However, as we have pointed out above, it is premature to draw any clinical conclusions from these data because of the limitations we have described and because more data will be forthcoming.

Directions for Future Research

Given this inability to draw clinical conclusions, we provide the next steps that should be undertaken in developing psychotropic research to the point that results can guide the clinical application of these drugs for neuroprotection. While it is not clear what the most predictive models of clinical neuroprotection are, and what the most important neuroprotective mechanisms are, it is apparent that some drugs are further along in their preclinical research than others. It is also clear that some seemingly paradoxical neuroprotective outcomes are seen, such as modafinil’s ability to increase glutamate release and yet reduce glutamate toxicity, and paroxetine’s ability to reduce hippocampal Aβ production in Alzheimer’s disease transgenic mice despite its anticholinergic properties that would otherwise tend to increase Aβ production. These seeming contradictions point to the need to focus on research findings rather than our current limited theoretical understanding. Thus, we outline the next research steps to be taken to elaborate findings that will move us toward establishing neuroprotective drugs that can be applied by clinicians.

Apathy Treatments

It would be of interest to investigate pramipexole in normal neurons, especially dopaminergic and cholinergic neurons.

Pramipexole should be better characterized as to its effects on αSyn, Aβ, tau, and Aβ fibril and oligomer-induced reactive oxygen species formation as well as on the proteasome and on mitochondrial metabolism. It then should be investigated in clinical neuroprotection paradigms in neurodegenerative disease, particularly Parkinson’s disease.

The next step for amantadine involves investigations in neurons.


Risperidone needs more study to determine its neuroprotective potential. Its ability to reduce Complex I activity in regions of the brain, albeit not in the midbrain, indicates the need for further research as to its long-term safety in neurodegenerative diseases affecting the hippocampus, frontal lobe, and striatum, including Alzheimer’s disease, frontotemporal lobar degeneration, and Huntington’s disease. Clinical effects tend to contraindicate its use in Parkinson’s disease.

Although olanzapine should be better characterized as to its multiple neuroprotective effects (especially on the proteasome and mitochondrial permeability transition pore development), antimuscarinic and parkinsonian clinical properties argue against its application in Alzheimer’s disease and Parkinson’s disease.

Quetiapine should be better characterized as to its effects on αSyn, Aβ, tau, the proteasome, and protection against rotenone toxicity. Further studies using Aβ and initial studies using MPP+ should be carried out, with subsequent disease-modification studies in Alzheimer’s disease and Parkinson’s disease if the preceding studies indicate safety, although antihistaminic and anticholinergic clinical properties can constitute a limitation to use in Alzheimer’s disease.

Trifluoperazine, chlorpromazine, and thioridazine might be further studied in situations where inhibition of mitochondrial permeability transition pore development is of utility.

Aripiprazole and ziprasidone should be studied for their neuroprotective properties, given their low proclivities to induce extrapyramidal side effects in people with neurodegenerative disease.

Mood Stabilizers

Lithium should be studied for neuroprotection in patients with Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and cerebral ischemia. A clinical trial in Alzheimer’s disease is currently under way.

Investigation of valproate’s ability to induce mitochondrial permeability transition pore development but not mitochondrial membrane depolarization or cytochrome c release may yield information that may help develop neuroprotective mitochondrial strategies.

Valproate might be investigated in patients with Parkinson’s disease and oncological diseases for its antiapoptotic effects in the former and proapoptotic effects in microglia and the latter. Valproate’s ability to increase αSyn concentrations may be either beneficial or detrimental in Parkinson’s disease and other synucleinopathies, and further research is needed. Activated microglia appear to be of importance in neurodegenerative diseases, especially Alzheimer’s disease. Results of a recent clinical trial in Alzheimer’s disease are not yet available.


Desipramine, nortriptyline, and maprotiline should be studied in other models of Huntington’s disease. If effective, they might be tried in other neurodegenerative disease models and in depressed patients with Huntington’s disease. Nortriptyline’s effects in Huntington’s disease yeast and amyotrophic lateral sclerosis mouse models deserve replication.

Fluoxetine has inhibited neural stem cell apoptosis, hippocampal apoptosis in newborn mice and rats and serotonin-induced apoptosis. Although it has some proapoptotic properties, fluoxetine should be studied further as a neuroprotectant in Alzheimer’s disease.

Paroxetine should be studied further for neuroprotective properties, especially in regard to reductions in Aβ and hyperphosphorylated tau.

Anxiolytics and Hypnotics

Buspirone has inhibited apoptosis in several neuronal models and now deserves study in regard to other related characteristics. If further studies indicate safety, studies in patients with neurodegenerative disease should then be undertaken.

Which types of GABA-A agonists protect against Aβ neurotoxicity and which do not requires clarification.

Clonazepam should be studied further for its restorative properties in Complex I deficiency, and should be better characterized in regard to apoptotic effects in neuronal models, especially on frontal lobe apoptosis in mature animals. If favorable results are forthcoming, it might then be tried in patients with neurodegenerative disease, especially Parkinson’s disease, although its association with falls in the elderly is a limitation.

Diphenhydramine should be further characterized in inflammatory, malignant, hypoxic, and other models where histamine plays a role.

Melatonin might now be investigated in patients with Alzheimer’s disease and in those with Parkinson’s disease.

Comprehensive Strategies

Deficiencies detailed in Table 5 deserve to be addressed in future studies. Validation of Table 6 translational predictive criteria awaits investigation. The relative predictive weightings of the various criteria also await outcome studies.

Combination therapies of psychotropics with differing profiles of neuroprotective actions may yield greater clinical impact than monotherapies. These varying profiles are depicted in Table 8. For example, across neurodegenerative diseases, the combination of lithium and melatonin might provide neuroprotective synergies, as might pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis, lithium, and desipramine in Huntington’s disease, and pramipexole, lithium, desipramine, and melatonin in Alzheimer’s disease (Table 8). In Alzheimer’s disease, lithium and melatonin together might synergize efficacy at Aβ, hyperphosphorylated tau, reactive oxygen species, transition pore development, and apoptosis, with lithium perhaps improving ubiquitylation. In Parkinson’s disease, this combination plus pramipexole may synergize benefits to reactive oxygen species, transition pore, and apoptosis, with lithium perhaps improving ubiquitylation and pramipexole and melatonin perhaps synergizing efficacy on αSyn. It should be remembered, however, that some combination therapies, applied in cancer chemotherapy, have sometimes resulted in a reduced efficacy of all drugs and an increase in side-effects.28 Animal trials of proposed combinations would be a first step in evaluating their safety and efficacy.

Progress Thus Far: Clinical Trials

So far, some preliminary progress has been made in identifying the clinical neuroprotective properties of some of these agents. A search performed on October 9, 2007 using the search terms “randomized clinical trial AND (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) for each drug revealed only one clinical neuroprotection study (ropinirole versus -dopa), and two studies evaluating glutathione reductase and a gamma interferon, relevant to disease progression, but without evaluating actual indices of clinical neuroprotection. A 6-18F-fluorodopa PET study of 186 patients with Parkinson’s disease randomized to either ropinirole or -dopa revealed a significant one third reduction in the rate of loss of dopamine terminals in subjects treated with ropinirole.29 A study of valproate plus placebo versus valproate plus melatonin in patients with epilepsy demonstrated a significant increase in glutathione reductase in the melatonin group, but no clinical indices of actual neuroprotection were evaluated in that study.30 A study in patients with relapsing-remitting multiple sclerosis identified a relationship between sertraline treatment of depression and attenuation of proinflammatory cytokine IFN-gamma, but again, actual indices of clinical neuroprotection were not assessed.31 In addition to the findings of the search, the CALM-Parkinson’s disease study involving the dopamine agonist pramipexole in Parkinson’s disease found faster progression (or at least less improvement on total UPDRS score) but slower dopamine transporter signal loss than with -dopa over 46 months,32 although the study has been criticized for lack of a placebo, group heterogeneity, and confounding influences on dopamine transporters. In contrast, a 2-year study of ropinirole found no significant difference in fluorodopa uptake compared to -dopa treatment (−13% versus −18%).33

A search of clinical trials (www.clinicaltrials.gov) on October 9, 2007 using the terms (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) and neurodegenerative diseases revealed only a few studies in progress. These included pramipexole in amyotrophic lateral sclerosis, early versus delayed pramipexole in Parkinson’s disease, and valproate in spinal muscular atrophy. Since that time, as of February 1, 2009, additional studies have been registered. In Alzheimer’s disease, these include a short-term study of CSF tau epitopes with lithium, brain volume and clinical progression with valproate, and hippocampal volume, brain volume, and clinical progression with escitalopram. In frontotemporal dementia, there is a single study of CSF and brain volume with quetiapine versus D-amphetamine. In Huntington’s disease, there is a study of CSF BDNF levels with lithium versus valproate. In dementia with Lewy bodies and Parkinson’s disease dementia (PDD), there is a study of clinical progression with ramelteon. In Parkinson’s disease, there is a study of striatal dopamine transporter by β-CIT SPECT with pramipexole versus -dopa while an 8 year study of disability with pramipexole has been terminated. Only the spinal muscular atrophy and dementia with Lewy bodies/PDD studies employ clinical neuroprotective designs (delayed-start paradigm), and the validity of biomarker correlates, particularly dopamine transporter measures in Parkinson’s disease, continues to be studied.

The discussion above relies on multiple investigative approaches using a number of different psychotropics in a variety of models and a diversity of cell lines. A major caveat is that preclinical results do not necessarily translate into clinical realities. For example, favorable preclinical findings for the neuroprotectant minocycline exist in Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, stroke, spinal cord injury, and MS models, but a recent phase III trial in patients with amyotrophic lateral sclerosis was halted because of a 25% faster rate of neurological progression with the active drug than with placebo.34 Nevertheless, some generalizations seem possible at this stage. The considerations above are offered in hopes of stimulating the identification and development of pharmaceuticals that are useful both for symptomatic improvement and for long-term neuroprotection in neurodegenerative disease. Pursuit of the directions for research suggested above may contribute to that development.


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