Enhancing the Power of Galantamine

Increasing the effects of an AChEI with choline precursors …

… with choline alphoscerate, CDP-choline, and other choline donors such as choline (as in choline citrate)

Researchers at the University of Camerino, Italy set out to determine if treatment with the acetylcholinesterase inhibitor (AChEI) galantamine and the cholinergic precursorcholine alphoscerate—alone or together—had any protective effect on brain microanatomy in spontaneously hypertensive rats used as an animal model of vascular dementia (hereafter dementia).1 That was back in 2009.

Alzheimer’s Breakthrough

Microanatomy is the branch of anatomy dealing with microscopic structures—in this particular instance—of the brain. This study confirmed a neuroprotective effect of galantamine in an animal model of dementia and indicates a neuroprotective role of choline alphoscerate in the same model.

Choline alphoscerate (also known as alpha-GPC) is a natural choline compound found in the brain. It is also a substance that stimulates the parasympathetic nervous systemand acts as an acetylcholine precursor. As such, it is thought to have potential for treating Alzheimer’s disease and other dementias. Choline is also a precursor molecule for the neurotransmitter acetylcholine, which is involved in many functions including memory and muscle control. It is sufficiently and inexpensively delivered in the form of choline citrate.

This study confirmed a 
neuroprotective effect of galantamine 
in an animal model of dementia 
and indicates a neuroprotective role 
of choline alphoscerate in 
the same model.

Amplified Neuroprotective Effect

Returning to the 2009 study,1 a wider neuroprotective effect of the acetylcholinesterase inhibitor/precursor (galantamine/choline donor) was observed. The association between the AChEI inhibitor galantamine with the cholinergic precursor choline alphoscerate increased acetylcholine levels dose-dependently more effectively than single compounds

By extrapolation, when galantamine is taken with any acetylcholine (ACh) precursor, galantamine should work even better—not only to reduce the deleterious effects of hypertension on brain degeneration, but to improve upon the balance of cholinergic reuptake and release mechanisms so necessary for optimum memory function. (See “Alzheimer’s Breakthrough” in the April 2012 issue.)

Choline is also a precursor molecule 
for the neurotransmitter 
acetylcholine.

Cholinergic Hypofunction and Alzheimer’s

Among the traits of Alzheimer’s disease (AD) and dementia is cholinergic hypofunction.Countering cholinergic hypofunction is one of the main therapeutic strategies for these disorders. Cholinergic transporters control cellular mechanisms of ACh synthesis and release it at presynaptic terminals.

A study published in 2012 assessed the influence of four weeks of treatment with two different cholinergic-enhancing nutrients—choline alphoscerate or galantamine—on high affinity choline uptake transporter and vesicular ACh transporter expression in the brains of spontaneously hypertensive rats.2 These rodents represent an animal model of cerebrovascular injury characterized by cholinergic hypofunction.

By extrapolation, when galantamine is 
taken with any acetylcholine 
(ACh) precursor, galantamine 
should work even better.

Increased Expression of Choline Transporters

Analysis was performed on the frontal cortex, striatum and hippocampus regions of rat brains. Immunochemical and ELISA (enzyme-linked immunosorbent assay) analysis was extended to peripheral blood lymphocytes (PBL), used as a peripheral reference of changes of brain cholinergic markers. ELISA is a test that uses antibodies and color change to identify a substance.

Cholinergic transporters control 
cellular mechanisms of ACh 
synthesis and release it at 
presynaptic terminals.

Expression of the choline transporters was increased in brain areas investigated and in PBL of the model rats used. The similar trend for cholinergic transporters in brain and PBL suggests that these cells are markers of brain cholinergic transporters.

Treatment with the cholinergic precursor choline alphoscerate increased bothtransporter expressions. Treatment with galantamine countered the increase of these transporters. The different activity of the cholinergic precursor and of the AChE inhibitoron parameters investigated is likely related to their mechanism of action.

Choline alphoscerate increases ACh synthesis and release, as do other ACh precursors. This requires an augmentation of systems regulating neurotransmitter uptake and storage. The effect of choline alphoscerate on the choline transporters observed in this study suggests an improved synaptic efficiency elicited by the compound.

Expression of the choline transporters 
was increased in brain areas 
investigated and in PBL.

Galantamine Slows Down ACh Utility

The AChE-inhibitor galantamine slows down ACh degradation in the synaptic cleft. A greater availability of neurotransmitter stimulated by galantamine counters the enhanced activity of cholinergic transporters compensating cholinergic deficits. Differences in the activity of the cholinergic precursor and AChE inhibitor investigated on the choline transporters suggests that association between choline alphoscerate and galantamine represents a strategy for potentiating deficient cholinergic neurotransmission. This is likely to be true for all cholinergic precursors, including CDP-choline (see below) and choline as choline citrate.

The effect of choline alphoscerate on 
the choline transporters observed in 
the studies discussed suggests an 
improved synaptic efficiency 
elicited by the compound.

Combination Cholinergic Therapy for Schizophrenia

Schizophrenia is another disease helped by an AChEI such as galantamine. However, it is only partially effective, and thus many people living with schizophrenia do not achieve full functional recovery. In particular, negative symptoms such as social withdrawal and blunted affect (this is a severe reduction in the intensity of affect; a common symptom of schizophrenic disorders), as well as disturbances of memory and attention still persist. These signs and symptoms contribute to poor social and vocational outcomes, leading to chronic disability.

In a recent study (August, 2013), researchers examined whether a selective α-7 nicotinic agonist intervention would improve negative symptoms and cognitive impairment associated with schizophrenia.3

Alpha-7 nicotinic acetylcholine receptor agonists, such as galantamine, may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. The alpha-7 nicotinic receptor is a type of nicotinic acetylcholine receptor implicated in long-term memory. Unfortunately, chronic exposure to this agonist may reduce the receptor’s sensitivity.

CDP-Choline Enhances Galantamine Efficacy

Consequently, the researchers combined CDP-choline—a dietary source of the direct agonist choline—with galantamine, a positive allosteric modulator of nicotinic acetylcholine receptors, designed to improve the efficiency of transducing the choline signal and to preserve the receptor sensitivity.

The establishment of a relationship 
between galantamine and a choline 
precursor that enhances both ACh 
synthesis and release is something 
that we have long thought about. 
The two primary papers cited in 
this article have finally 
offered more support.

They conducted a clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second-generation antipsychotics (risperidone was most commonly prescribed).

Forty-three subjects received galantamine and CDP-choline or matching placebos for 16 weeks. The primary outcome measure was the negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). PANSS is a medical scale used for measuring symptom severity of patients with schizophrenia.

Cognition and functioning were also assessed. A total of 79% completed the trial. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery, which is intended to provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia and related disorders.

There were significant treatment effects in overall functioning and a test of free verbal recall. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning.

Long Expected

The establishment of a relationship between galantamine and a choline precursor that enhances both ACh synthesis and release is something that we have long thought about. The two primary papers cited in this article have finally offered more support. That’s all the better for those who ardently seek to preserve their memory function. It’s about time.

References

  1. Tayebati SK, Di Tullio MA, Tomassoni D, Amenta F. Neuroprotective effect of treatment with galantamine and choline alphoscerate on brain microanatomy in spontaneously hypertensive rats. J Neurol Sci. 2009 Aug 15;283(1-2):187-94.
  2. Tomassoni D, Catalani A, Cinque C, Di Tullio MA, Tayebati SK, Cadoni A, Nwankwo IE, Traini E, Amenta F. Effects of cholinergic enhancing drugs on cholinergic transporters in the brain and peripheral blood lymphocytes of spontaneously hypertensive rats. Curr Alzheimer Res. 2012 Jan;9(1):120-7.
  3. Deutsch SI, Schwartz BL, Schooler NR, Brown CH, Rosse RB, Rosse SM. Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy. Schizophr Res. 2013 Aug;148(1-3):138-44. doi: 10.1016/j.schres.2013.05.023. Epub 2013 Jun 13. PubMed PMID: 23768813; PubMed Central PMCID: PMC3732552.