141 replies to this topic

[NeuroGuy]

I hate being the guy to bring up negative findings, but I've had some doubt cast on galantamine and the rest. Read the following findings..

- Nicotine increases tau through activation of p38-mitogen-activated protein kinase.

http://www.ncbi.nlm....pubmed/15705720

c Natl Acad Sci U S A. 2005 Feb 22;102(8):3046-51. Epub 2005 Feb 10.

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease.
Oddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, Leslie FM, LaFerla FM.

Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.

Abstract
The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on Abeta accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on Abeta and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of alpha7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of alpha7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal Abeta(42) accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either Abeta or tau.

PMID: 15705720 [PubMed - indexed for MEDLINE]PMCID: PMC549455

- 7nAChR mediated down-regulation of CREB, through ERK MAPK cascade.

http://www.jneurosci...hort/21/12/4125

The Journal of Neuroscience, June 15, 2001, 21(12):4125-4133


-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal 7 Nicotinic Acetylcholine Receptors: In Vitro and In Vivo Mechanisms Related to Alzheimer's Disease
Kelly T. Dineley1, Marcus Westerman3, Duy Bui1, Karen Bell1, Karen Hsiao Ashe2, 3, and J. David Sweatt1
1 Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and Departments of 2 Neurology and 3 Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455

Alzheimer's Disease (AD) is the most common of the senile dementias, the prevalence of which is increasing rapidly, with a projected 14 million affected worldwide by 2025. The signal transduction mechanisms that underlie the learning and memory derangements in AD are poorly understood. -Amyloid (A) peptides are elevated in brain tissue of AD patients and are the principal component of amyloid plaques, a major criterion for postmortem diagnosis of the disease. Using acute and organotypic hippocampal slice preparations, we demonstrate that A peptide 1-42 (A42) couples to the mitogen-activated protein kinase (MAPK) cascade via 7 nicotinic acetylcholine receptors (nAChRs). In vivo elevation of A, such as that exhibited in an animal model for AD, leads to the upregulation of 7 nAChR protein. 7 nAChR upregulation occurs concomitantly with the downregulation of the 42 kDa isoform of extracellular signal-regulated kinase (ERK2) MAPK in hippocampi of aged animals. The phosphorylation state of a transcriptional mediator of long-term potentiation and a downstream target of the ERK MAPK cascade, the cAMP-regulatory element binding (CREB) protein, were affected also. These findings support the model that derangement of hippocampus signal transduction cascades in AD arises as a consequence of increased A burden and chronic activation of the ERK MAPK cascade in an 7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.

I don't think I need to explain the implications for the first article. The second article basically says that chronic a7 stimulation results downstream in the down-regulation of CREB, which memory is hugely dependent on. Maybe this partly is why a7 agonists improve memory so effectively, short-term increase in CREB protein phosphorylation.

Giving Alzheimers patients AchE Inhibitors might, and I emphasize MIGHT, be similar to giving l-dopa to Parkinsons patients. Yes it improves symptoms by directly increasing the deficient transmitter, but also causes more damage through one of, if not thee, primary cause of the patholoy (toxic dopamine metabolism in parkinsons). Increasing a7 binding in Alzheimers could potentialy worsen symptoms in the long run, and predispose healthy individuals to it.

Thoughts?

Edited by NeuroGuy, 24 September 2010 - 08:15 PM.

[chrono]

Increasing a7 binding in Alzheimers could potentialy worsen symptoms in the long run, and predispose healthy individuals to it.

It's a possibility that deserves more scrutiny, but I don't think it should necessarily be that alarming. Both of these studies used models specific to AD, so I'm not sure how much the concern can be applied to healthy subjects. Maybe there are more papers that can paint a more generally applicable picture.

Edited by chrono, 26 September 2010 - 04:48 AM.

[Rational Madman]

Increasing a7 binding in Alzheimers could potentialy worsen symptoms in the long run, and predispose healthy individuals to it.

It's a possibility that deserves more scrutiny, but I don't think it should necessarily be that alarming. Both of these studies used models specific to AD, so I'm not sure how much the concern can be applied to healthy subjects. Maybe there are more papers that can pain a more generally applicable picture.

Yes, this is an example of what I warned of---jumping to premature conclusions. Because even if nicotinic receptor upregulation leads to the increased aggregation and phosphorylation of tau proteins, there are other pharmaclogical targets that can mop up the damage, while still lending Alzheimer's subjects the necessary therapeutic benefit of increased receptor activation. My sage advice, less monotherapy, and more polypharmacy. More importantly, look at the body of evidence as a whole, and not selected results. This is not to say that selected contradictory findings are false, but in my experience, an adventurous mind can effectively manage the incidence of possible adverse events. Receptor stimulated effects on CREB, for example, could be managed with Rolipram, Rasagiline, and a powerful promoter of neurotrophic factors. For tau, I would say Rember looks most promising, but we'll have to await the results of ongoing trials.

Edited by Rol82, 26 September 2010 - 12:17 AM.

[someidiot]

Ahh...nicotine/smoking. If such didn't lead to premature aging--i'd be a chimney!

[Rational Madman]

Statins appear to be a good candidates for alpha7 receptor upregulation, but does anyone have any personal experience with this class? I have a few reservations, but I'm amenable to changing my mind.

[NR2(x)]

I found "- 7nAChR mediated down-regulation of CREB, through ERK MAPK cascade" to be very interesting as it may highlight the causative reason behind nicotines ability to reduce beta-amyliod. I understand Beta-amyliod to be a response to excessive Long Term Potentiation, where by the system achieves a messy kind of Long Term Depression to maintain temporal plasticity. If nicotine reduces LTP then this would eliminate the role of Beta-amyliod and hence decrease production and viability. I know this isnt at the scientific level required

[chrono]

Did some reading this morning to try to figure out how much of a concern the tau protein issue may be. First, it's worth noting that nicotine seems to have an overwhelmingly positive effect on ambyloid-beta, which is perhaps responsible for the generally inverse relationship between smoking and AD. For a quick picture, nicotine is capable of inhibiting amyloid-beta formation [1] [2] [3] [4] [5] [6], and attenuating its neurotoxicity [7] via a4b2 [8] and a7 agonism [9] [10]. Nicotine can also increase the secretion of the 'helpful' amyloids [11] [12], and is neuroprotective independent of a7 activation [13] via directing binding to the proteins [14] [15] and regulation of metal homeostasis [16]. However, as a cholinergic it can increase general amyloid secretion [17], and is able to both enhance [18] and attenuate [19] amyloid's reduction of LTP.


The rest of the papers examining tau hyperphosphorylation:

Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists.
Hellström-Lindahl E, Moore H, Nordberg A.

Several cholinesterase inhibitors used in the treatment of Alzheimer's disease (AD) have been shown to interact with an allosteric site on the nicotinic acetylcholine receptor (nAChR). A possible linkage between the phosphorylation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72 h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M), and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M) increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The increased tau immunoreactivity induced by tacrine was not prevented by atropine, indicating that in terms of cholinergic receptors, tacrine modulates tau levels mainly through interactions with nAChRs and not with muscarinic receptors. Additional work is needed to determine the exact mechanism by which cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and levels of tau protein.

PMID: 10646530 [PubMed - indexed for MEDLINE]

alpha7 Nicotinic receptor gene delivery into mouse hippocampal neurons leads to functional receptor expression, improved spatial memory-related performance, and tau hyperphosphorylation.
Ren K, Thinschmidt J, Liu J, Ai L, Papke RL, King MA, Hughes JA, Meyer EM.

Brain alpha7 nicotinic receptors have become therapeutic targets for Alzheimer's disease (AD) based on their memory-enhancing and neuroprotective actions. This study investigated the feasibility of increasing neuronal alpha7 receptor functions using a gene delivery approach based on neuron-selective recombinant adeno-associated virus (rAAV)-derived vectors. In order to determine whether alpha7 receptor-mediated cytotoxicity was dependent on receptor density, rat alpha7 nicotinic receptors were expressed at high concentrations in GH4C1 cells as measured with nicotine-displaceable [3H]methyllycaconitine (MLA) binding. The potency of GTS-21 (an alpha7 receptor agonist) to induce cell loss was similar in these cells to that seen in pheochromocytoma (PC12) cells expressing nine-times-lower receptor levels, suggesting that cytotoxicity was more dependent on agonist concentration than receptor density. Hippocampal transduction with rat alpha7 nicotinic receptors increased [3H]MLA binding in this region in wild type and alpha7 receptor-knockout (KO) mice without apparent cytotoxicity. No difference was observed in Kd values for MLA binding between endogenous and transgenic receptors. Single cell recordings demonstrated that dentate granule cells that normally have no alpha7 receptor response did so following alpha7 receptor gene delivery in wild type mice. Recovery of alpha7 function was also observed in stratum oriens and stratum radiatum neurons of KO mice following gene delivery. Wild type mice exhibited improved acquisition performance in the Morris water task 1 month after bilateral hippocampal transductions with the rat alpha7 receptor gene compared with green fluorescent protein-transduced controls. However, both groups reached similar training levels and there was no difference in subsequent probe performance. Finally, this gene delivery approach was used to test whether alpha7 receptors affect tau-phosphorylation. Chronic (i.e. 2 month but not 2 week) expression of high levels of alpha7 receptors in hippocampus increased AT8 staining characteristic of hyperphosphorylated tau in that region, indicating that endogenous agonist-mediated receptor activation may be able to modulate this process.

PMID: 17218065 [PubMed - indexed for MEDLINE]

Nicotine exacerbates tau phosphorylation and cognitive impairment induced by amyloid-beta 25-35 in rats.
Deng J, Shen C, Wang YJ, Zhang M, Li J, Xu ZQ, Gao CY, Fang CQ, Zhou HD.

Nicotine was reported to reduce the plaque burden and could be used as a possible anti-Alzheimer's disease agent. However, the effect of nicotine on memory and tau pathology in Alzheimer's disease has been less studied. The present study investigated the effect of nicotine on tau phosphorylation and cognitive impairment induced by hippocampus injections of amyloid-beta (Abeta) 25-35. Rats were treated with nicotine hydrogen tartrate salt dissolved in normal saline by subcutaneous injection twice per day for 14 days. The age and gender matched rats treated with same amount of normal saline were used as the control. Morris water maze was used to detect the cognitive impairment induced by Abeta25-35. Compared to the sham-operated rats, Abeta25-35 injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test and increased the number of tau(pS202) and tau(pT231) immunoreactive cells. The data show that nicotine (1mg/kg in base weight) treatment significantly exacerbates cognitive impairment and tau phosphorylation at Ser-202 and Thr-231 in the hippocampus compared with Abeta25-35 injection groups in the Abeta rat model of Alzheimer's disease. The use of nicotine for treatment of Alzheimer's disease should be reassessed.

PMID: 20363218 [PubMed - indexed for MEDLINE]

One conclusion to be drawn (based on this limited data) is that hyperphosphorylation seems to be a general effect of a7 upregulation, and not of nicotine in particular. Another (from the second paper) is that the period of treatment is a critical factor; cycling may be something to consider.

Several points can be made about the paper posted by neuroguy, above. First, these were 3xTg-AD mice, who are pre-doomed to begin developing AD rather early in life (6 months). Exacerbating a pre-existing mechanism may be a far cry from elevating this to a concern for the healthy. This is also suggested by the third paper I posted, in which nicotine exacerbates amyloid-generated tau tangles. Second, the doses used in this study were a little high; figuring on a 20g mouse drinking 5mL water per day [http://www.ncbi.nlm....es/PMC1397713/], the oral dosage was ramped over the first month to 150mg/kg (or 12mg/kg human equivalent), and maintained there for 5 months. I would be surprised if different effects aren't produced by a dose 300x higher than my own.

So I think the possible issue with tau hyperphosphorylation should be kept in mind, but probably isn't a huge concern if these drugs are used carefully.

Statins appear to be a good candidates for alpha7 receptor upregulation, but does anyone have any personal experience with this class? I have a few reservations, but I'm amenable to changing my mind.

Given their checkered reputation, is there anything that would make this class of drugs attractive, except perhaps their availability?

Edited by chrono, 26 September 2010 - 10:40 AM.

[aLurker]

Very intersting post chrono and I'm glad the concern was brought up.

I was going to post here about my initial impressions with nicotine and nicotine in conjunction with galantamine but it became too long and would probably derail this excellent thread so I posted it as this thread instead.

[someidiot]

Statins appear to be a good candidates for alpha7 receptor upregulation, but does anyone have any personal experience with this class? I have a few reservations, but I'm amenable to changing my mind.

Well, from observations of my smoking mother who is on statins,...let's just say that the woman infact 'breathes' instead of smokes... and I don't notice any improvement intellectually.

[NeuroGuy]

Chrono,
Thank you for those points about my post, I should of taken the time to review before posting and I did jump to a premature conclusion as Rol82 said.

Any thoughts on the CREB down-regulation, pointed out in that second study? They are predisposed transgenic mice but might still be worth consideration.

[Rational Madman]

Statins appear to be a good candidates for alpha7 receptor upregulation, but does anyone have any personal experience with this class? I have a few reservations, but I'm amenable to changing my mind.

Given their checkered reputation, is there anything that would make this class of drugs attractive, except perhaps their availability?

From what I read, Lovasartin was the drug that produced the upregulation, but we need to delve deeper, and determine if it possesses additionally exceptional properties relative to others within this class. This finding also begs the question, is increased lipid metabolism a pathway to upregulation? If that's indeed the case, I think I might be onto something far reaching with my research on nuclear receptor agonists---which might constitute an important missing link in comprehensive cognitive enhancement.

Edited by chrono, 29 September 2010 - 10:40 AM.
trimmed quote

[Rational Madman]

Chrono,
Thank you for those points about my post, I should of taken the time to review before posting and I did jump to a premature conclusion as Rol82 said.

Any thoughts on the CREB down-regulation, pointed out in that second study? They are predisposed transgenic mice but might still be worth consideration.

The suggestions that I provided in my previous posting should address the possible CREB downregulation problems. But, nicotine administration at higher doses has been repeatedly demonstrated as a sustainable learning enhancer. And as you might find in neuroscience, neurochemical functions like memory encoding are not monocausal, and thus, entirely dependent on the CREB protein. Allow me to impart some more sage advice: complicated problems have multiple dimensions, and although monocausality has the allure of providing solace providing and easily comprehensible answers, the explanatory power never fails to be limited in such models. Of course, you're aware of this, but my point is, try not to become fixated on pathways, and don't allow confounding variables to stop you if a modality possesses merit.

Edited by Rol82, 27 September 2010 - 03:42 AM.

[NeuroGuy]

Chrono,
Thank you for those points about my post, I should of taken the time to review before posting and I did jump to a premature conclusion as Rol82 said.

Any thoughts on the CREB down-regulation, pointed out in that second study? They are predisposed transgenic mice but might still be worth consideration.

The suggestions that I provided in my previous posting should address the possible CREB downregulation problems. But, nicotine administration at higher doses has been repeatedly demonstrated as a sustainable learning enhancer. And as you might find in neuroscience, neurochemical functions like memory encoding are not monocausal, and thus, entirely dependent on the CREB protein. Allow me to impart some more sage advice: complicated problems have multiple dimensions, and although monocausality has the allure of providing solace providing and easily comprehensible answers, the explanatory power never fails to be limited in such models. Of course, you're aware of this, but my point is, try not to become fixated on pathways, and don't allow confounding variables to stop you if a modality possesses merit.

Your right, and that is great advice. I've spent months at a time pursuing misleading research because of fixation on individual (and later irrelevant) pathways. The message hasn't sunk in apparently.

Anyways, not to hijack this thread. Maybe I'l give Galantamine a trial after all.

[KimberCT]

Stumbled across this today...

Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats.

Polesskaya OO, Smith RF, Fryxell KJ.

Center for Biomedical Genomics & Informatics, Department of Molecular & Microbiology, George Mason University, Manassas, Virginia 20110, USA.
Abstract

BACKGROUND: Previous data in humans and animal models has suggested connections between anxiety, depression, smoking behavior, and nicotine dependence. The importance of these connections has been confirmed by clinical studies that led to the recent FDA approval of an anti-depressant (Zyban) for use in human smoking cessation programs. Other anti-depressants (such as rolipram) specifically inhibit PDE4 phosphodiesterases.

METHODS: We used DNA microarrays to discover gene expression changes in adolescent female rats following chronic nicotine treatments, and real-time PCR assays to confirm and extend those results.

RESULTS: We found a consistent decrease in the mRNA levels encoded by the Pde4b gene in nucleus accumbens, prefrontal cortex, and hippocampus of adolescent female rats treated with .24 mg/day nicotine, and in prefrontal cortex of adolescent female rats treated with .12 mg/day nicotine. We further show that each of these brain areas produced a different profile of Pde4b isoforms.

CONCLUSIONS: Chronic nicotine treatments produce a dose-dependent down-regulation of Pde4b, which may have an antidepressant effect. This is the first report of a link between nicotine dependence and phosphodiesterase gene expression. Our results also add to the complex interrelationships between smoking and schizophrenia, because mutations in the PDE4B gene are associated with schizophrenia.

PMID: 16814262

[Rational Madman]

Chrono,
Thank you for those points about my post, I should of taken the time to review before posting and I did jump to a premature conclusion as Rol82 said.

Any thoughts on the CREB down-regulation, pointed out in that second study? They are predisposed transgenic mice but might still be worth consideration.

The suggestions that I provided in my previous posting should address the possible CREB downregulation problems. But, nicotine administration at higher doses has been repeatedly demonstrated as a sustainable learning enhancer. And as you might find in neuroscience, neurochemical functions like memory encoding are not monocausal, and thus, entirely dependent on the CREB protein. Allow me to impart some more sage advice: complicated problems have multiple dimensions, and although monocausality has the allure of providing solace providing and easily comprehensible answers, the explanatory power never fails to be limited in such models. Of course, you're aware of this, but my point is, try not to become fixated on pathways, and don't allow confounding variables to stop you if a modality possesses merit.

Your right, and that is great advice. I've spent months at a time pursuing misleading research because of fixation on individual (and later irrelevant) pathways. The message hasn't sunk in apparently.

Anyways, not to hijack this thread. Maybe I'l give Galantamine a trial after all.

Well, you're certainly not the first person here to become fixated on ultimately trivial or incomplete etiologies---many do---so, don't be hard on yourself. If you have Lyme Disease, Galantamine would be a good investment, because I remember reading something about an alteration in acetyltransferase activity. I would talk to FunkOdyssey, though, whom has the distinction of being the resident Lyme Disease expert.

Edited by Rol82, 29 September 2010 - 08:29 AM.

[chrono]

@NeuroGuy: I don't know why you should feel admonished. Nothing about your post struck me as fixating or jumping to conclusions. You don't have to spend 6 hours doing a literature review to raise a potentially critical possibility. Discussion of research seems like a better antidote to premature conclusions, rather than sweeping concerns under the carpet before they're even properly elucidated.

Still have some points about galantamine I'd like to return to, but first, I want to touch on a few other nicotinergic agents I've been meaning to talk about for a while:

Nefiracetam

Zhao et al. (2001) conducted a good study, and also integrated other findings up to that point into their discussion. They found nefiracetam to potentiate a4b2 currents in rat frontal cortex neurons, in a way that did not require receptor activation. An initial peak in current was followed by a much longer plateau of effect. The minimum required concentration was 0.1nM, and exhibited a bell-shaped dose-response up to about 10uM: (% current evoked by 10uM ACh)

The degree of potentiation was independent of ACh concentration. The effect was dependent upon activation of G_s proteins (and not G_i/G_o, or PKA and PKC), but the mechanism at the nAChR receptors was not elucidated (~5 possibilities raised in discussion). These findings on mechanisms contrast with several of the preceding studies (see below), but the authors note that nAChR structure and characteristics are highly dependent upon the host cell type; it appears to be unknown whether native rat cells or human cells cloned in species like Xenopus more closely model the effect in humans.

Unfortunately, nefiracetam also inhibited a7 currents irreversibly (at least in this model; some activation was found in other studies). 1uM inhibited current to 2.8%, 10uM to 8.7%, and 100uM to 20.1%. With a dosage of 200mg, peak serum levels in humans was 16.3±0.9 uM, and 0.98-4.89uM for the three main metabolites. Half-life was 3.9h, and 7.8-21.9 for the metabolites [1]. If we assume that the CSF/brain levels will be somewhat lower than this, the a7 inhibition may be somewhere in the range of 2-8% with a 200mg dose. However:

Nefiracetam displays the highest efficacy for nicotinic enhancement at levels from 1-1000nM (i.e. .001-1uM), and potentiates NMDA at 10nM [2] and 1uM [3]. Thus, a much lower dose (say, 5-10x?) might suit the purposes of nicotinic potentiation much better, reduce the possible a7 inhibition to negligible levels, and further obviate concerns about toxicity (which appeared at doses many times higher than even the normal human dose, to begin with).

Another interesting question is raised by two papers (last two in the following list) which compare nefiracetam and galantamine directly. Galantamine's potentiation of a4b2 currents was limited to 15-20%, compared to several hundred by nefiracetam. It also had a greater effect (at 100x lower concentration) on miniature post synaptic currents, which probably come closer to modeling actual effects on synaptic activity.

All this makes nefiracetam an interesting possibility, I think—though there are some lingering safety concerns which have been discussed in other threads (see thread index), and still need more examination (also probably best in other threads). Here are summaries of the rest of the studies concerned with nAChR, which present some varying numbers, activations and mechanisms based on the types of cells:

[Facilitatory actions of the cognitive enhancer nefiracetam on neuronal Ca2+ channels and nicotinic ACh receptors: their intracellular signal transduction pathways] (Yoshii et al)
1uM nefiracetam enhanced N/L-type Ca2+ channels though G proteins and cAMP pathways. In Xenopus, 10-100nM produced depression of signals, while 1-10uM potentiated them; the depression was caused by cAMP-dependent PKA, and the potentiation by Ca2+ and PKC. This suggests brain concentrations above .1uM should be targeted, to cover all bases.

Modulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam (Oyaizu & Narahashi 1998)
Observed potentiation of 10uM ACh from 0.1 to 10uM of nefiracetam in PC12 cells, and suppressing effects at 100uM of nefiracetam or 100uM+ ACh. In contrast to Zhao et al, the effect was found to be dependent upon PKA and G_i/G_o proteins.

A 'long-term-potentiation-like' facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetam. (Nishizaki et al 1999)
Nefiracetam enhanced excitatory postsynaptic potentials in rat HIPP CA1 slices to 170% for at least 4h, and for 16h after IM injection to rats. The effect was blocked by ACh antagonists and PKC inhibitors, but not NMDA antagonists. Though independent of NMDA, saturated enhancement of synaptic potentials occluded the effect of induction of LTP by other means.

Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission. (Nishizaki et al 2000a)
1-10uM nefiracetam potentiated currents in Torpedo Xenopus ACh and a4b2/a7 nicotinic receptors, through PKC phosphorylation of receptors. The sustained enhancement led to increased glutamate release, and LTP in HIPP.

Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action. (Noruma & Nishizaki 2000)
Dose-dependently facilitated neutrotransmission in rat HIPP DG from 1nM to 1uM (in a way similar to aniracetam and piracetam, so not indicative of nAChR). In Xenopus, nefiracetam potentiated a3b2, a3b4, a4b2, a4b4, and a7 to "different extents."

The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors. (Nishizaki et al 2000b)
Potentiated current through a4b2 a7 in Xenopus through PKC. In rat HIPP neurons, it increased the rate of mEPSC without affecting the amplitude, produced a long-lasting facilitation of synaptic transmission in CA1 and DG, and increased presynaptic glutamate release.

Mechanisms of action of cognitive enhancers on neuroreceptors. (Narahashi et al 2004)
Re-caps the previous work by this group (Narahashi, Moriguchi, Zhao, etc). Galantamine potentiated a4b2 current at 100nM-1uM, though not as potently as nefiracetam, being limited to 15-20% of the control current.

Nefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons. (Moriguchi et al 2009)
10nM nefiracetam increased the frequency of mEPSC and mIPSC without affecting the amplitude. 1uM galantamine did not potentiate the frequency.

Aniracetam

Zhao et al (1999) found that aniracetam paralleled nefiracetam's nicotinic effects. 10uM irreversibly inhibited 20.8±6.7% of a7 current, and 0.1nM-10uM markedly potentiated a4b2. The minimum dosage for potentiation was less than 0.1nM.

Nishizaki et al (2000a) found no potentiation of either nicotinic subtype in Xenopus, and Noruma & Nishizaki (2000) observed no effect on a7. This makes it questionable whether aniracetam is an effective nicotinic potentiator, but if so, supports the use of small doses for this purpose.

Herbs

Crude extracts of ginseng were found to displace nicotine from nAChR, with an IC50 of 2.12mg/mL; the effect was due to non-ginsenosides portion of the extracts [4]. Ginsenosides (esp. Rg2) and their metabolites (esp CK and M4) inhibited ACh current at a3b4, a3b2, a4b4, and a4b2, but not a7 [5] [6] [7] [8] [9]; ginseng also inhibited nicotine-evoked release of catecholamines [10] [11].

Salvia officinalis is thought to interact with nicotinic systems [12], though based on behavioral observations, rather than mechanism.

Lemon balm (melissa officinalis) was able to displace nicotine at receptors [13], though conflicting reports render the effect and its clinical significance doubtful [14] [15] [16].

Artemisia absinthium exerted an either nicotinic or muscarinic effect [17]

Edited by chrono, 02 October 2010 - 07:03 PM.

[aLurker]

Yep. Since we've spoken of other racetams. Oxiracetam also seems to be of interest:

Oxiracetam prevents mecamylamine-induced impairment of active, but not passive, avoidance learning in mice.

The nicotinic antagonist mecamylamine (2.5 and 5 mg/kg/IP) depressed both active (shuttle-box) and passive (step-through) avoidance learning in mice of the DBA/2 strain. The nootropic drug oxiracetam (50 and 100 mg/kg/IP) improved acquisition in the multitrial active avoidance test, but had no effect on one-trial passive avoidance learning. When the two drugs were combined, oxiracetam did not counteract mecamylamine-induced impairment of passive avoidance learning, even if it maintained a facilitating action on shuttle-box avoidance acquisition in mice receiving the nicotinic receptor blocker. Prevention of mecamylamine-induced shuttle-box avoidance depression by oxiracetam indicates that central nicotinic mechanisms are probably involved in the improving effects exerted by nootropic drugs on learning.

Effects of oxiracetam-nicotine combinations on active and passive avoidance learning in mice.

Tested alone, in CD-1 mice, the nootropic drug oxiracetam (50 mg/kg) improved learning in a multitrial active avoidance task (shuttle-box), but did not affect one-trial passive avoidance acquisition. Nicotine, which was ineffective at the dose of 0.25 mg/kg, improved both active and passive avoidance at the dose of 0.5 mg/kg; 1 mg/kg nicotine still exerted facilitating effects on passive avoidance, but slightly depressed shuttle-box performance. Combinations of oxiracetam and nicotine improved passive avoidance more than either drug given separately. In the active avoidance task, a combination of oxiracetam with the lower dose of nicotine exerted improving effects never observed with nicotine alone, even at higher doses. The nootropic drug also prevented the slight depressant action exerted by 1 mg/kg nicotine. Thus, contrary to what was previously supposed, at least in mice subjected to shuttle-box avoidance training, nicotinic activation does not appear as the main neurochemical mechanism involved in the action of oxiracetam. Perhaps, oxiracetam and nicotine activate different types of cholinergic mechanisms, but it cannot be excluded that other neurotransmitters, particularly catecholamines, may be involved in the avoidance facilitating effects produced by nicotine and by combinations of the two drugs.

I'd love to see a study regarding what nAChRs might be affected by oxiracetam!

Edited by aLurker, 02 October 2010 - 11:22 AM.

[medievil]

Damn, now ive got galantamine i ran out of nicotine! Could have been an interesting combo.

[medievil]

Ive been interested in the aniracetam/nefiracetam stack wich seems highly synergystic, will try that on top of memantine, nicotine and galantamine, could be interesting.

[KimberCT]

 Given my experience with antiemetics, I can't believe I forgot about this one.  Tropisetron is a 5-HT3 antagonist and α7-nicotinic partial agonist.... haven't seen it for sale anywhere though.  Would really love to try it for its purported ability to reduce Substance P levels as well. 

Edited by KimberCT, 06 October 2010 - 11:46 PM.

[medievil]

Whats it intrinsic activity?

[KimberCT]

Whats it intrinsic activity?

It looks like the data is in the linked article, but I don't have access to the full text.

[Rational Madman]

Given my experience with antiemetics, I can't believe I forgot about this one. Tropisetron is a 5-HT3 antagonist and α7-nicotinic partial agonist.... haven't seen it for sale anywhere though. Would really love to try it for its purported ability to reduce Substance P levels as well.

Yeah, I I made a reference about this affinity in a different thread. But do you realize how expensive a month's supply is without a prescription? Assuming that it's administered once every two days, the monthly cost should be approximately $600. It's currently undergoing clinical trials for a few neuropsychiatric conditions, and besides that, though, I haven't seen evidence that the drug does anything spectacular. Through its mechanism. it should help with information processing and certain categories of memory, but I get the feeling that the treatment of nausea is going to be its primary indication.

Edited by Rol82, 07 October 2010 - 01:24 PM.

[KimberCT]

Given my experience with antiemetics, I can't believe I forgot about this one.  Tropisetron is a 5-HT3 antagonist and α7-nicotinic partial agonist.... haven't seen it for sale anywhere though.  Would really love to try it for its purported ability to reduce Substance P levels as well.

Yeah, I I made a reference about this affinity in a different thread.  But do you realize how expensive a month's supply is without a prescription?  Assuming that it's administered once every two days, the monthly cost should be approximately $600 a month.  Its currently undergoing clinical trials for a few neuropsychiatric conditions, and besides that, though, I haven't seen evidence that the drug does anything spectacular.  Through its mechanism. it should help with information processing and certain categories of memory, but I get the feeling that the treatment of nausea is going to be its primary indication.

I haven't seen it for sale anywhere so I wasn't aware of the price.  I do have an Rx for ondansetron which is only about $20/mo. without insurance.  Granisetron, which is also generic now, is about twice as much.

[aLurker]

Ive been interested in the aniracetam/nefiracetam stack wich seems highly synergystic, will try that on top of memantine, nicotine and galantamine, could be interesting.

Sounds very interesting. As I'm very interested in improving executive function and increasing motivation I found this patent about about treating apathy with racetams very interesting.

Preferred compounds include nefiracetam, piracetam, aniracetam, and oxiracetam, of which nefiracetam is most preferred.

EXAMPLES Example 1 Treatment of Apathy in Post-Stroke Patients

The activity of nefiracetam to improve apathy and/or cognitive function in post-stroke patients has been demonstrated by a controlled clinical trial against placebo. In this trial, nefiracetam was administered orally to 103 post-stroke patients, who all have some degree of depression, for up to twelve weeks after the vascular event. Concurrently, 56 patients received placebo (placebo group). Of the 103 post-stroke patients treated with nefiracetam, 55 received 600 mg daily (600 mg group), and 48 received 900 mg daily (900 mg group). The three groups of patients were followed for up to 12 weeks, and evaluated at the end of week 4, the end of week 8, and the end of week 12, by measuring the Apathy Evaluation Scale (a symptom scale for measuring apathy), and by measuring SDMT (for measuring cognitive function).

There was a dose-dependent and time-dependent change in apathy syndrome for the nefiracetam-treated patients in comparison to the placebo group, where larger numeric changes mean larger improvements in apathy. As of the last visit (12 weeks), the 900 mg group showed an average improvement of 3.4 points, the 600 mg group showed an average improvement of 2.1 points, and the placebo group showed an average improvement of 1.4 points. In comparison, at 4 weeks, the 900 mg group showed only a 1.9 point improvement in apathy, the 600 mg group showed only a 1.9 point improvement, and the placebo an average improvement of 1.4 points.

The change in apathy was also more marked for patients who were treated within 28 days of the stroke, where the 900 mg group showed an average improvement of 6.1 points, the 600 mg group showed an average improvement of 1.3 points, and the placebo group showed an average improvement of 0.6 points. Nefiracetam worked particularly well in improving apathy for patients who had suffered cortical strokes. At the last visit carried forward, the 900 mg group of cortical stroke patients showed an average improvement of 5.2 points, compared with 3.4 for the 600 mg group and 1.0 for placebo. Last visit carried forward is a standard method of data analysis whereby patient drop-outs are dealt with by using the value obtained at the patient\'s last actual visit as the value for all subsequently scheduled, but missed, visits when no data could be collected.

When patients with cortical strokes and significant baseline apathy (greater than 18) were studied, the improvement in apathy in the 900 mg group was 11.7 points at the last visit, compared with 9.4 points in the 600 mg group and 5.4 points in the placebo group.

Nefiracetam also showed dose-dependent and time-dependent improvements in cognitive function as measured by the SDMT. As of the last visit, the 900 mg group showed an average improvement of 6.6 points, the 600 mg group showed an average improvement of 5.7 points, and the placebo group showed an average improvement of 4.2 points. In comparison, at 4 weeks, the 900 mg group showed only a 4.4 point change, the 600 mg group showed only a 4.1 point change, and the placebo group showed only a 3.2 point change. The improvements in cognitive function were more marked for patients with cortical strokes. The improvement seen in the SDMT scale in the 900 mg group for patients with cortical strokes was 14.2 points at week 12, in comparison with 7 points in the 600 mg group at week 12, and 2.7 points for the placebo group at week 12.

The clinical findings thus show that in the treatment of post-stroke patients, the treatment should be initiated as early as possible, preferably within the first few months, and preferably as soon as possible, e.g., within the first month following the stroke event.



Example 2 Treatment of Apathy in Depression Patients

In 151 post-stroke patients having moderate to severe depression, the intervention-free data of Apathy Scale (AS), as a valid measure of apathy, and of Hamilton Rating Scale of Depression (HAM-D) and Beck Depression Inventory (BDI), as valid measures of depression, were collected and analyzed using the method of confirmatory factor analysis. HAM-D and BDI are fully validated and are widely used measures of the severity of depression. HAM-D (Hamilton, J Neurol. Neurosurg. Psychiatry. 23:56-62, 1960) is rated by a professional. BDI (Arch Gen Psychiatry. 4:561-571, 1961) is rated by a patient.

The 151 patients, who were evaluated at least once after treatment, included the 103 patients studied in Example 1. The 151 patients were divided in three groups each orally receiving placebo (51 patients) or nefiracetam at 600 mg/day (54 patients) or nefiracetam at 900 mg/day (46 patients).

The data at the end of 12 weeks were analyzed and summarized as follows:

(a) As time went, patients\' apathy measured by the Apathy Scale declined from pre-treatment for patients on active treatments as well as for patients on placebo; however, patients on active treatment, especially on the high dose medication, showed more reduction in apathy than did patients on placebo. This finding is consistent across patients with moderate to severe depression and patients with severe depression, and the treatment effect appears to have occurred early for more depressed patients; (b) As time went, patients\' apathy measured by the Apathy Scale declined from pre-treatment for patients on active treatments as well as for patients on placebo; however, patients on active treatment, especially on the high dose medication, showed more reduction in apathy than did patients on placebo. This finding is consistent across patients with various severity of baseline apathy, and the treatment effect appears to have been slightly large for more severe patients. © As time went, patients\' depression measured by HAM-D declined from pre-treatment for patients on active treatments as well as for patients on placebo; however, unlike the treatment effects observed on patients\' apathy, patients on placebo showed slightly more reduction in depression than did patients on active treatment. This finding is consistent across patients with various severity of baseline apathy, and the placebo effect appears to have been slightly larger than the treatment effect, especially for patients on the lower active dose. The results indicate apathy and depression are distinguishable entities.

I'm not entirely convinced regarding the long-term safety of nefiracetam, especially considering the issues in animal studies. Personally I'd consider it safe enough to try once or twice but I wouldn't consider it for long-term use. Pramiracetam looks cool but also unknown. I've ordered some aniracetam and oxiracetam though since they both seem very safe. I'll probably also do some experimenting with nicotine, galantamine and some racetams (pi/ani/oxi) along with ALCAR.

ALCAR might also have some synergy in that mix:

From Neuroprotective effects of acetyl-L-carnitine on neuropathic pain and apoptosis: A role for the nicotinic receptor:

In conclusion, ALCAR presents both analgesic and antihyperalgesic properties mediated by the cholinergic pathway. Nevertheless, although analgesia can be viewed as a muscarinic effect, the antineuropathic effect is completely reverted by mecamylamine-mediated blockade of the nicotinic receptor. The nicotinic mechanism is also responsible for a significant, but not complete, part of the apoptotic-preventing effect of ALCAR. ALCAR is a clinical compound with a good safety profile, so the nicotinic component of ALCAR pharmacodynamic properties is free of compromising adverse effects.

[medievil]

Nefiracetam is safe in normal doses, the dog ball study doesnt mean much, i'l try to look up some refs (also about the nefiracetam/aniracetam stack wich a few ppl tried on mind and muscle and found very synergetic).

[aLurker]

Oh, I'll also post this list of potential research interests on the subject of alpha 7 agonists:

Taken from the patent: "COMBINATIONS OF NICOTINIC ACETYLCHOLINE ALPHA 7 RECEPTOR AGONISTS"

[0075] In a preferred embodiment, the combination according to the invention comprises one nicotinic acetylcholine alpha 7 receptor agonist and one antidepressivum. [0076] In a particularly preferred embodiment, the combination according to the invention comprises compound (A) and one or more, preferably one, compound selected from the group consisting of agomelatine, azapirones, alprazolam, amitriptyline, aniracetam, acetyl-L-carnitine, aripiprazol, acetophenazine, benzodiazepines, barbiturates, buspirone, bupropione;chlordiazepoxide, chlorazepate, clonazepam, chlorpromazine, Clozaril, CX614, CX516, chlorprothixene, diphenydramine hydroxyzine, demoxepam, diazepam, droperidol, duloxetine, donezepil, doxepine, desipramine, flurazepam, fluphenazine, fluoxetine, flupentixol, gabapentine, melatonin, ginko-derived compounds, galantamine, haloperidol, hydergine, huperzine, isocarboxazid, imipramine, lorazepam, loxapine, meprobamate, medazepam, moclobemide; molindone, maprotiline; modafinil, memantine, methylphenicate, mesoridazine, mesoridazine, methotrimeprazine, nortriptyline, naproxene, oxazepam, oxiracetam, olanzapine, prazepam, paroxetine, phenelzine, pipotiazine, perphenazine, promazine, pimozide, PDE4 inhibitors, quazepam, quetiapine, reboxetine, rivastigmine, rochiorperazine, risperidone, sertraline, sertindole, temazepam, triazolam, tranylcypromine, tomoxetine, thiotixene, trifluoperazine, thioridazine, Zolpidem, ziprasidone.

Taken somewhat out of context from the patent and I'm sure not all of them are entirely relevant yet I feel this could give us a hint regarding substances which might be worth looking into since the list is quite comprehensive and the patent is very relevant to this thread.

[chrono]

I just posted a summary of nefiracetam's toxicity here. It turns out that one study (a year-long one) found evidence of toxicity at below the human equivalent of two standard dosages per day, though from the abstract it's not clear precisely how toxic we're talking. Lower dosing as outlined above might be desirable, or occasional usage if higher doses are necessary for efficacy.

Regarding the two oxiracetam papers aLurker posted (by the same authors), the second one says: "Thus, contrary to what was previously supposed, at least in mice subjected to shuttle-box avoidance training, nicotinic activation does not appear as the main neurochemical mechanism involved in the action of oxiracetam." So, it seems somewhat unlikely that there's much chance of nicotinergic activity, though it might be a good adjunct for low dosages of aniracetam or nefiracetam.

And regarding our old friend piracetam, a not-so-happy finding:

[Effects of piracetam and meclofenoxate on the brain NMDA and nicotinic receptors in mice with different exploratory efficacy in the cross maze test]
Kovalev GI, Firstova IuIu, Salimov RM.

A population of outbred mice of the ICR strain was divided into two subpopulations according to their high (EH mice) or low (EL mice) exploratory efficacy in the closed cross maze test. In addition, the EH and EL mice differed in the number of binding sites of (i) [G-3H]-MK-801 with NMDA receptors from hippocampus and (ii) [G-3H]-nicotine with nicotine cholinoreceptors (nACh) from neocortex. A subchronic administration of the cognition enhancer piracetam (200 mg/kg, once per day for 5 days) increased by 70% the number of binding sites of NMDA receptors in the EL mice. At the same time, this treatment decreased the density of neocortical nACh receptors in both EL and EH mice (by 55% and 40%, respectively). A subchronic administration of the cognition enhancer and anti-oxidant meclofenoxate (100 mg/kg, once per day for 5 days) also decreased the density of neocortical nACh receptors in both EL and EH mice (by 48% and 20%, respectively). However, meclofenoxate also increased by 41% the number of binding sites of NMDA receptors in the EH mice.

PMID: 18365480 [PubMed - indexed for MEDLINE]

Edited by chrono, 07 October 2010 - 04:32 PM.

[aLurker]

And regarding our old friend piracetam, a not-so-happy finding:

Thanks for informing us. Anything indicating whether aniracetam or oxiracetam also could decrease the density of nACh receptors?

I'm thinking oxiracetam or a combination of ani and oxi could be a much better choice for me personally since although piracetam seems to give me focus and clarity I've long suspected it to be very slightly de-motivational or in best case neutral in my own subjective experience. I've been looking through a lot of meds/nootropics looking for anything described as increasing motivation and piracetam is basically the only racetam not attributed with that, for me very desirable, property. A very rare thing for something that seems to increase mental vigor and focus. The study you posted above might be the explanation.

Edited by aLurker, 07 October 2010 - 06:18 PM.

[aLurker]

Targeting Nicotine Receptors to Treat Cognitive Impairments in Schizophrenia

From TFA:

In their study of healthy monkeys, Graham Williams and colleagues at Yale University and AstraZeneca found that very low doses of AZD0328, a novel drug that acts as an alpha-7 agonist, produced both acute and persistent improvements in their performance on a spatial working memory task.