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Neurotrophins and Cardiovascular Health
by: Andreas Martin

In recent years there’s has been lot of discussion around neurotropic factors and modulators. In this article I expand on the general understandings of how neurotropics are modulated and to show new avenues to memory improvement.

In general terms many research pharmacologists and supplement fanatics have put a lot of effort to achieve a higher mental state whilst supplementing and selfmedicating with various BDNF and NGF altering pharmaceuticals. The result haven’t always yielded major effects; which might be due to an incomplete understanding of how such mechanisms work. One important fact is that very little is known about how certain drugs should be applied under certain circumstances; more specifically, what some of the key factors behind memory formation and its extension are.

This brief review article is divided into two sections. The first part describes a few interesting possibilites regarding cardiovascular drugs in the treatment of cognitive impairment; and the second part describes systematically, neurotrophin activation in general.

Cardovascular effects on memory

Background

Cardivascular health has been the subject of intense investigation for many years. Health does not only mean a good physicue but has been associated with above average mental perfomance. In these next topics I have summarized some of the most important key factors that either modulate or enchance neurotropic potential and increase memory span.

Betablockers and working memory

Cardiac drugs such as beta blockers have been succesfully used in panic disorders and situations where social interactivity is involved. Some evidence suggest that using betablockers are helpful before critical situations, wherein calmness and aquity are needed. Such facts suggest that betablockers generally could have some central nervous system activity which in some circumstances might be helpful when correctly recognised.

Long term propranolol use has been cited as effective and safe compared to benzodiazepines which have potent negative impact on cognitive function. Especially important is the fact that the use of beta blockers doesn’t inhibit memory processing whereas benzodiazepines do. The general mechanism of betablockers seems quite obvious, however the exact mechanisms are not yet clearly understood. Whilst the possible involment of GABA, dopamine and serotonin have been considered, I believe the most intriguing area worth researching is beta blockers, and how they interfere with hypothalamic activation.

The most prominent mechanism of betablockers would be the inhibiton of both central and peripheral renin secretion which is altered thorough betaadreneric stimuli. Such inhibiton shuts down SNS activation, causes a drop in blood pressure and diminishes the monoaminergic system in general.

But how does such intervention interfere with memory processing? Recent evidence suggest that memory processing is under control of complicate of neurohormonal and neuromodulational elements. Among neuropeptides the most prominent contributor might be the vasopressin (12). Vasopressin, more specifically arginine [8]-vasopressin [1-9], is a nine amino acid long neurohypophysial hormone, which is commonly associated with osmotic water balance and blood pressure; and has more recently been shown to act as a neuromodulator and neurotransmitter in the CNS (12), where it has been associated with cognition and memory consolidation. Vasopressin injections have shown to increase memory span both in animals and humans (18). Vasopressin is widely distributed around the brain and most densely found in the hypothalamus. Similary to monoamines, vasopressin has been found in postsynaptic vesicles where it acts like a neurotransmitter (19).

In the CNS, vasopressin is under heavy influence of dopamine, NE, 5HT and angitensin (4). Vasopressin peptidergic transmission originates from the supraoptic and paraventricular nuclei and evolves into the hippocampus, whereas the hormonal release of vasopressin is directed to the posterior pituary (9), where it triggers hypophyseal vasopressin release. The cerebral connectivity of vasopressin is positively linked with sex hormones (both androgens and estrogens), and inhibited by excessive cortisol (15).

The involvement of beta blockers in vasopressin regulation seems to be linked to the direct inhibiton of angiotensin/dopamine pathways, whereas it could affect concomittant release of other neurotransmitters and regulate the effects of sex hormones. Moreso, it has been shown that beta blockers are able to revese some of the dysfunctional dopamine syndromes aka extrapyridamyl symptoms – EPS. It turns out that both the inhibiton of dopamine and reduction of sex hormones contribute to lessen memory retention while the suppression of angitensin and concomittant increased force of peptidergic vasopressin release have been postulated to increased memory performance (7,15). Renin-angitensin and memory

As previously mentioned, angiotensin is one of the main controllers of vasopressin release. Converting enzyme inhibitors and angiotensin receptor blockers have been postulated to increase cardiac protection, mental wellness and to potentiate antiaging drugs (8). They also help in shifting catabolic wasting to the anabolic phase and have many numerous extra benefits. Until recently it was not know if such drugs affected memory. ICV injections of ANGII to water-deprived mice have been shown to increase water seeking behaviour and decline in performance and memory retrieval(14).

Renin, which is another peptide in the renin-angiotensin cascade (along with increased ANGII levels) have been shown to disrupt memory formation (7, 14). Such an outcome was blocked with co-application of captopril and AT1 antagonist losartan. Both angiotensin and renin enchanced previously disrupted performance of rats that were treated either with shock avoidance behaviour or immobilization stress, following training on the pluss maze. Theoretically (in some instances), fully blocking renin secretion would avoid memory deterioration. Athe available findings suggest that decreasing the AT1 receptor modulation may faciliates cognitive functioning or prevent it cognitive damage. Empirical findings have shown that ACE inhibitors and/or AT1 antagonists may be useful to improve cognitive function on humans with impaired memory.

Mineralocorticoids and androgens on working memory

Aldosterone as a key mineralocorticoid is a strong antidiuretic steroid which works concomittantly with vasopressin. While excessive levels of aldosterone indicate possible dysregulations of hypothalamus and may contribute to depressive behaviour (6), the loss of aldosterone indicates lower vasopressin and increased corticosterone activity; which could consequently supress memory. A study was conducted where rats were given chronical intracerebroventricular injecetions of aldosterone antagonist, spironolactone (20). The results showed 20% decreased memory perfomance in water maze test compared to littermates. Along with angiotensin, the most prominent effect of aldosterone has been associated to the expression of the two most important hormones in the hypothalamus – corticotropin releasing hormone (CRH) and arginine-vasopressin (AVP). I am not able to conclude if aldosterone suppresses or induces sex hormones. The general effect of aldosterone on androgens is supportive since it does hold on water. From bodybuilding communities it is well accepted that some androgens like nandrolone act similar to aldosterone while others like stanazol and masteron may suppress it.

One of the mechanisms where the body activates aldosterone receptors is as a reconiliator at the presence of overactive renin and angiotensin system. In other words, if renin-angiotensin begins to dominate, the aldosterone helps to balance it. Thus another A int RAS cycle, the renin-angiotensin-aldosterone system. There happens to be a very strong bond with neuroendocrine activation and inhibition. While aldosterone increases body water weight it may also help maintain vasopressin activity in the hippocampus by supressing corticosteroids (20). This would also indicate to a increase of memory formation.

These particullar steroids give us the same perspective of how androgens and aldosterone work hand in hand. There’s definitely a relation with both of these substances and perhaps a very clear example how steroid and peptid hormones react to each other. It has been cited that aldosterone along with androgens is one of the key elements in hypothalamic and hippocampal regulation.

The role of neurotrophins

Background

Neurotrophins (NTs) are proteins responsible for the growth and survival of neurons during brain development and maintenace. In the near future, the continious improvement of our understanding of neurotrophin activation will oopen up exciting possibilites on how to learn to control such devastating brain disorders like Alzheimer’s, Parkinson’s and senile dementia.

Both in vitro and in vivo studies show that NTs are involved in the restoration of impaired neural network. The effect of NTs are divided into two subsystem: Eiter the neuron itself is able to release protective neurotrophins on its own (which is named as a autocrine support), or it needs extra support from astorcytes (which is paracrine support). Probably the most effective stimulation originates from the latter because astrocytes are more accustomed to such activity.

The regulation of paracrine activation is controlled both by targeted cytokine and neurotransmitter/neuromodulators acitvation through direct genomic regulation; whereas the second role would be to give some perspective of other higher dimension regulators like tubular systems and extracellular orintation. These roles are discussed below.

Neurotrophins and neurotransmitters

BDNF and dopamine

Dopamine D1 receptors have been postulated as BDNF activators and main triggers of BDNF upregulation (3). It has been cited that people suffering Parkinson’s disease have decreased BDNF trophic activity in the nigral dopaminergic neurons (16). In vitro studies have shown through immunoassays that the supportive role of astrocytes are suppressed to nonexistent levels in some of the Parkinson’s patients (16). The intracellular interaction between neurons and astrocytes play a crucial part for the brain development and maintenance. The main paracrine support is carried out by neurotrophins but is controlled by the neurotranmitters. Dopamine has the releasing ability of NTs from the astrocyte intracellular matrix, especially BDNF. This phenomena explains the possible pathological changes in Parkinson’s model where BDNF levels are lowered (7). The effect of dopamine turns out to be the most motivating but has the most potent effect on neural upregulation which eventually could end up having serious lesions(7).

NGF and histamine

One of the intriguing neurochemicals in the brain is histamine. While it is released mostly from mast cells after allergic reactions, it has also the ability to activetate NGF pathways.

Histamine happens to be a powerful vasodilator which may contribute to it’s neurotropic ability. A possible explanation is that the NGF receptor contains traces of Ig-x receptor domains which may faciliate histamine’s role in NGF expression. Of course in pathological situations it might be devastating. Excessive NGF activation could result in a allergic reaction or concomittant brain disorder due to astrocyte swelling. The same goes for BDNF expressing astrocytes but lesser extent.

One of the most notable features of NGF is its direct relation to neurohormones like aldosterone and corticosterone. In the near future it could be foudn to have some important effect on cognition control and brain inflammation. The most two notable pathologies that would be treated in the near future with NGF modulation are ill-effected states of immunomodulation and inflammation caused by localised lesions (16).

BDNF, glutamine, GABA and cytokines

There’s some supportive data that glutamine/GABA transmission helps to control and modulate neurohormonal expression in the supraoptic nucleus of the hypothalamus. It has been shown GABA and glutamine as the one of the most important upregulation of neurotrophins especially BDNF (1). In differents studies it has been shown that kainic acid agonism is an example to the most potent up-regulator of BDNF mRNA expression in these neurons (16). The same overview article showed the relation between intracellular activation and BDNF upregulation. A succesful survey was also conducted on forskolin, whose effects were measured by PKC and phospholipase A2 intracellular content. It turned out that forskolin does faciliate BDNF signalling potency probably through cAMP activation (16). In this study it was also noted that in vivo effects of cytokines TNF-? and IL-1?, IL-4, IL-6 and TGFb1 increase BDNF and NGF cellular contents (17).

Magnocellular BDNF and NGF expression

A well known substances which yields the toxic effects of fly agar is the ibotenic acid. Some data suggest that toxicoses caused by the iboteinic acid are produced by localized lesions in the hypothalamus through nonselective AVP and OT expression (2). Such effects could lead to hypothalamic malfunctioning and development of neurodegenative disorders. They are also good for producing neurodegenrative models of a malfunctional hypothalamus. Such effects can be reversed by faciliating the expression of CNF – ciliary neurotrophic factor, a magnocellular survival factor (10) or by treatment with sarsapogenin a known phytochemical by elevationg low M1 muscarinic receptor density in brains (11). Possibel involment of AT1 and AT2 receptors in the magnocellular regulation is under investigation. One study revealed the possible relationship between dopamine D1 receptor and angiotensin AT1 receptor density (7). The same study revealed the possibilty that dopamine D2 presynaptic receptors could be faciliated with AT1 activition leading to increased dopamine levels and consequently D1 activation (4,8). Thus it could be theorized that the integrity of the dopamine system in magnocellular system is under control of angiotensin peptides. This of course could open up a completely new avenue of cures for mental illnesses and would bring us closer to the mechanisms which drive cognitive impairment like ADHD. Especially important would be discovering how angiotensin and dopamine regulate memory and behavioural activity in such impaired psychiatric models.

Angitensin and Extracellular matrix

Extracellular matrix molecules (ECM) are collagen related adhesion molecules whcih have been cited as the mainframe for neural networking and development. Such dimensions control the paracrine support of astrocytes and also control the general movement of neural connectivity. I hereby would make a comparison to highway circulation and ECMs in nervous system. The activation of matrix metalloproteins (MMP), which are group of proteolytic enzymes, are the key elements for maintenance and restructuring of the ECM. MMPs requires zinc for enzymatic activity while the proper cleavage of this propeptide is done by the serine proteinases and other MMPs. The whole process implicates physiological processes like angiogenesis and wound healing. MMPs are likely involved in the pathophsysiology of CNS diseases including memory deterioration and Alhzeimer’s disease. There’s a third group of mainframe molecules. They are called cell adhesion molecules (CAMs). These are macromolecules that mediate cell-to-cell´and cell-to-ECM contacts through adhesion, migration, neurite outgrowth, synaptogenesis and intracellular signalling and eventually memory consolidation (14). All three constitue to the higher mechanisms of neural regulation and neurotrophin feeding system. Though the activation of ECM is under control of another growth factor, it shows the complexity of the neurotrophin family.


Illustration 2. The regulation of main neurotrophin activities. The noticeable role of this illustration is to show the two different levels of such regulation. The activation of either NGF or BDNF is driven by the neural network of ECMs, while the micro circulation is carried out by the neurotransmitters. There’s some supportive data that ECM activation is under direct control of angigenesis and tubular formation driven by both AT1 and AT2 receptors; giving us a important look into how angitensin might impact neurotrophic regulation.

Conclusion

The topics discussed have revealed several important regulations of memory function which could be associated with cardiovascular effect. The beta adrenergic system and renin-angiotensin systems, along with aldosterone and androgens play a major role in memory formation in the CNS. There’s also enough evidence of the renin-angiotensin system’s involvement in the process of neurotransmitter modulation and neurotrophin faciliation. This review article aslo showed some bottlenecks and dangers of excessive NGF modulation and the complexity of the neurotrophin regulation.
References

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