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Friday, February 20, 2015

Prucalopride; A Safe EnteroKinetic Compound with Anti-Depressant and Nootropic Properties



This article has been exclusively written for TrueLIFE Research - TeamTLR.com and to foster further progress within research of 5-HT4 agonist compounds.


Prucalopride is a novel enterokinetic compound and is the first representative of the benzofuran class(1). It is a high-affinity (pK(i)  8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptor, respectively) human serotonin 5-HT(4) agonist and is shown to alleviate chronic constipation and exert fast-anti-depressant effects(2)(3). It also is shown to have nootropic properties, and has benefits in reversing scopolamine related memory deficits(4).
Prucalopride has shown efficacy & safety in treating gastrointestinal disorders in both the elderly and the young(5)(!).

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NEURO-GASTRO-ENTEROLOGY Is Relevant & Ecstatic About 5-HT4 Agonist Compounds
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NeurogastroEnterology has been an exciting field, especially in recent years -  given the circumstances surrounding recurring states of chronic constipation have yielded the observation of nerve pathways playing a primary role in the pathophysiology of constipation; including but not limited to pseudo and chemical intestinal obstruction.

Low serotonin is also on the rise, and is a major contributor to constipated states, including those with a psychological manifestation(6)(7).

Prucalopride and other 5-HT4 agonists thus are exciting developments and substantial checkpoints in the successful treatment of chronic constipation, including those states normally considered to be "treatment resistant"(8).

Because they don't rely on the body's ability to produce serotonin, and the compounds; like prucalopride don't bind to any other serotonin receptors - these are incredibly useful research tools and even more significant treatment methods....they produce considerably fewer side-effects, to the point where a side-effect profile might as well be called almost completely absent(9) (10)(11).



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PRUCALOPRIDE & Other 5-HT(4) Agonists as Potentiators and Stand-Alone Anti-Depressants; Bridging the Gap to Safer, and Innovative Depression Treatments
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While SSRI's certainly have made their name all throughout, and represent a major area of study in terms of depression - they also have many side-effects; including negative effects on cognition and paradoxical worsening of depression in some patients(12) (13).

Apathy and anhedonia are not uncommon consequences of SSRI treatment, which can lead to deterioration in quality of life for many patients(14) (15).

Additionally, they are associated with a number of other unfavorable side-effects, such as tachycardia(fast-heart-rate), bradycardia (abnormally slow-heart-rate), blood glucose abnormalties, changes in lipid profiles, and hormonal spectrum disturbances; including metabolic syndrome, cortisol excess (hypercortisolism) and  reduced testosterone production and subsequent loss of libido(16) (17) (18) (19).

Part of the problem, again, with SSRI's is non-specificity in receptor targeting/modulation.

Studies published in 20072010 and 2013+ are confirming that 5-HT4 agonists; including prucalopride - have immense anti-depressant effects, can enhance dopamine levels instead of decreasing it (20), and have vasodilating properties as opposed to vasoconstrictive or aggregating properties.

They also improve hippocampul function instead of degrading it, as SSRI's do, and thus are novel cognitive enhancing substances(21).



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Prucalopride Enhances Acetylcholine, Histamine and Dopamine Release ; 
                EVIDENCE FOR POTENT PRO-COGNITIVE EFFECTS
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Prucalopride , in a major study, was cited to significantly increase histamine, acetylcholine and dopamine in the hippocampus, as well as having positive effects in the reward circuitry of the striatum(22)(23).

Histamine and Acetylcholine are two primary area's of interest in regards to cognitive disorders; and are considered "two side's of the same coin"(24). Both of these neurotransmitters promote wakefulness, vigilance, and memory retention as well as active memory function...they also interact with each other a whole lot(25).

Two worthy quotes are displayed below.


The forebrain cholinergic neurons are localized in the nucleus basalis magnocellularis (NBM), the major source of cholinergic innervation to the neocortex and to the amygdala, and in the medium septum-banda diagonalis complex, which provides cholinergic inputs to the hippocampus (Mesulam et al. 1983; Woolf et al. 1984; Nicoll 1985). Basic and clinical studies have linked dysfunctions of these neurons to cognitive decline (Everitt and Robbins 1997; Givens and Sarter 1997). Their extensive loss is characteristic of the forebrain of Alzheimer's disease patients (Davies and Maloney 1976; Coyle et al. 1983; Kuhl et al. 1999), and anticholinergic drugs, such as scopolamine and atropine, produce learning and memory deficits in a variety of cognitive animal models (Deutsch 1971; Bartus and Johnson 1976; Ennaceur and Meliani 1992), and affect recognition memory in humans (Sperling et al. 2002; Sherman et al. 2003). Moreover, aged rodents display both cognitive impairments in many learning tasks (Ingram et al. 1994) and cholinergic deficits (Kubanis and Zornetzer 1981; Decker 1987; Gallagher and Colombo 1995). 


 Some histaminergic neurons also store neuroactive substances and related enzymes, such as GABA (Ericson 1991), glutamate decarboxylase (Takeda et al. 1984), adenosine deaminase (Senba et al. 1985), substance P (Köhler et al. 1985) and galanin (Köhler et al. 1986), in a species-specific manner (Airaksinen 1992), but the functional significance of these colocalizations is unknown at the moment. The morphological features of the central histaminergic system, with a compact cell group and a widespread distribution of varicose fibers, resembles that of other biogenic amines, such as norepinephrine and serotonin, thus suggesting that the histaminergic system may also act as a regulatory center for whole-brain activity (Wada et al. 1991). 


Considering the hypothalamus is a central brain region involved in hormone output, histamine is the subject of recent interests in neuro-endocrine disorders(26). Histamine is shown to be directly coupled to GnRH neurons(27), and thus, substances that activate it may help promote testosterone production, which may provide a further anti-depressant benefit(28).

Thus, an indirect increase in hypothalamic neuron activity (and hormone secretion) may represent one novel mechanism by which prucalopride may exert additional anti-depressant and pro-cognitive effects(29).



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PRUCALOPRIDE Potently Increases cyclic Adenosine Monophosphate (cAMP)
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Further supporting the clinical benefits of prucalopride on depression and on the hormonal axis, is it's ability to (much like forskolin) - potently increase cellular and central levels of cyclic AMP; which will lead to enhancement of metabolism and mobilization of blood glucose...(30) (31)

Stimulating cyclic AMP may lead to a net increase in steroidogenesis and an increase in overall thermal metabolism, which adds to the benefits and diversity of prucalopride and other 5-HT4 agonists(32) (33).

While there are no direct studies relating 5-HT4 agonists to testosterone secretion, it may be replicated in future studies where cAMP-based interactions are further examined(34) (35).



In summary, prucalopride may yield the following benefits.



  • Alleviate multiple forms of treatment resistant constipation and pseudo-gastro-intestinal obstructions.
  • Act as a potent and fast acting anti-depressant. 
  • Act as a synergist for other anti-depressants.
  • Improve Vigilance and cognitive function.
  • Reverse scopolamine related memory impairment and augment SSRI actions in the hippocampus.
  • Increasing levels of the valuable second messenger ; cyclic AMP.
  • Increasing dopamine, acetylcholine, and histamine levels.
  • As a potential metabolism enhancing compound.

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