Angiotensin II in the Brain & Therapeutic Considerations

In a previous post I suggested that another cheap generic drug (an ACE inhibitor) could potentially be repurposed to treat schizophrenia and some autism. The original idea was related more to modifying the immune/inflammatory response in the body, rather than the brain.  There is however plenty of research regarding Angiotensin within the brain and the numerous roles it plays.

Juggling - maximizing effects, while minimizing
drug interventions

You may recall in the earlier post that in both schizophrenia and autism there is elevated angiotensin II.

In the brain there are two types of angiotensin receptor, AT1 and AT2.  Their actions are opposing each other.

In many kinds of disease we would want to stimulate AT2, but inhibit AT1.

AT2 is thought to be important for cognitive function and is now a target for Alzheimer’s research.

Using an ACE inhibitor you reduce the amount of angiotensin II and so in effect inhibit both AT1 and AT2.

In theory angiotensin II should not cross the blood brain barrier (BBB), so we should be dealing with centrally produced (i.e. inside the brain) angiotensin II.  In practical terms it seems that people with high levels of angiotensin II may have a permeable BBB.

This is relevant because most ACE inhibitors do not cross the BBB, but the original ACE inhibitor called Captopril does cross the BBB.  So if a centrally acting ACE inhibitor were found to be required, it was discovered 40 years ago.

A therapy would ideally be targeted selectively at AT1 or AT2 receptors.  An AT1 blocker might treat for stress-induced disorders.  An experimental AT2 receptor agonist, called compound 21, is now available and is expected to reduce inflammation and oxidative stress.

Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo.

Angiotensin II receptor AT1 antagonists are widely used drugs indicated for hypertension, diabetic nephropathy and congestive heart failure. They block effect of Angiotensin on AT1 and might be good in the brain.

We would like to increase the effect on AT2, we could do that with more Angiotensin II, but then we would make things worse with AT1.

                          Do nothing  ACE inhibitor    AT1 antagonist      AT2 agonist

Effect on AT1               none                            good                                     good                          none

Effect on AT2               none                            bad                                       none                          good

AT1 antagonists are widely available and seen as well tolerated.

AT1 antagonists appear to protect against Alzheimer’s.

The only AT2 agonist is an experimental drug called Compound 21.

The only ACE inhibitor that should affect AT2 in the brain is Captopril and so may be an unwise choice. It will reduce Angiotensin II in the brain and in the rest of the body.


Why were we interested in Angiotensin?

Targeting Angiotensin in Schizophrenia and Some Autism

In the original Angiotensin post in this blog we saw that in schizophrenia and some autism, that Angiotensin II is elevated.  We also saw that:-

·        Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1, Th2 and Th17. 

·        In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

·        It should also reduce any troubling high levels of leptin, which we saw in another post is an issue in most autism

So the idea was that many broadly anti-inflammatory effects of reducing Angiotensin II might be helpful in autism.

But what about inside the brain?

Angiotensin in the Brain

Here we do get to the science, but I will start with the conclusion. We actually want more effect from the Angiotensin AT2 receptor, which should give numerous benefits, but have no means of achieving this. What we can do is make sure we do not reduce AT2 activity, this means better to use and AT1 antagonist, rather than an ACE inhibitor.

The science supporting the use of an AT agonist follows:-

In the text you will see ARB and compound 21. Both are doing good things. The suggestion is that by doing all these good things there should be improved cognitive function; this has yet to be proved in human tests.

ARB = Angiotensin Receptor AT1 Blocker

Compound 21 = Angiotensin Receptor AT2 agonist

Roles of Brain Angiotensin II in Cognitive Function and Dementia

The brain renin-angiotensin system (RAS) has been highlighted as having a pathological role in stroke, dementia, and neurodegenerative disease. Particularly, in dementia, epidemiological studies indicate a preventive effect of RAS blockade on cognitive impairment in Alzheimer disease (AD). Moreover, basic experiments suggest a role of brain angiotensin II in neural injury, neuroinflammation, and cognitive function and that RAS blockade attenuates cognitive impairment in rodent dementia models of AD. Therefore, RAS regulation is expected to have therapeutic potential for AD. Here, we discuss the role of angiotensin II in cognitive impairment and AD. Angiotensin II binds to the type 2 receptor (AT₂) and works mainly by binding with the type 1 receptor (AT₁). AT₂ receptor signaling plays a role in protection against multiple-organ damage. A direct AT₂ receptor agonist is now available and is expected to reduce inflammation and oxidative stress and enhance cell differentiation. We and other groups reported that AT₂ receptor activation enhances neuronal differentiation and neurite outgrowth in the brain. Here, we also review the effect of the AT₂ receptor on cognitive function. RAS modulation may be a new therapeutic option for dementia including AD in the future.

Figure 1: Possible effect of angiotensin II on neurovascular unit. AT₂: angiotensin II type 2 receptor, AchR: acetylcholine receptor, BBB: blood brain barrier, and TGF-β: transforming growth factor β.

Figure 2: Effect of angiotensin II type 2 receptor signaling on cognitive function. AT₂: angiotensin II type 2 receptor, ATIP: AT₂ receptor-interacting protein, Id1: inhibitor of DNA binding protein 1, MMS2: methyl methanesulfonate-sensitive 2, NO: nitric oxide, SHP-1: Src homology 2 domain-containing protein-tyrosine phosphatase 1, and Ubc-13: ubiquitin conjugating enzyme 13.

Figure 3: Effect of angiotensin II on cognitive function. ACE: angiotensin converting enzyme inhibitor, AT₁: angiotensin II type 1 receptor, AT₂: angiotensin II type 2 receptor, and ARB: angiotensin II type 1 receptor blocker.

Continuous stimulation with angiotensin II may damage neurons via multiple cascades through AT₁ receptor stimulation. On the other hand, stimulation of the AT₂ receptor is expected to prevent neural damage and cognitive impairment (Figure 3). However, it is difficult to perform clinical intervention studies to confirm the results of animal studies because of the long-term progression of cognitive impairment. Moreover, in clinical practice, it is not possible to exclude the antihypertensive effect of RAS blockade on cognition in patients with hypertension. However, RAS modulation may be a new therapeutic option for dementia including AD in the future. Therefore, the hypothesis that RAS regulation affects future cognitive function should be confirmed with carefully designed clinical studies.

Which ARB (Angiotensin Receptor Blocker) for Autism?

Very many biological markers are disturbed in autism and many of them seem to be best ignored, you cannot “correct” them all.

However, there will be an underlying reason behind each one of them being disturbed.

As we saw in the recent post on metabolic syndrome, it is not uncommon to find a cascade of downstream problems that might seem to indicate a huge list of drugs.  A different approach is required, it is necessary to treat the underlying (upstream) problems and have a much shorter list of therapies.

We saw in the post on leptin that the elevated levels in autism are treatable, but is there any point?

We have a long list of other things that might be useful in autism and it would be nice to have a single therapy that might address many of them.

It appears that selecting the optimal ARB might give the opportunity to address numerous issues at once.

Telmisartan seems to have numerous potentially useful additional effects:

·        Acts as a PPAR gamma agonist, like the glitazone drugs shown effective in autism trials

·        Acts as a PPAR delta agonist, which should activate the impaired PPARδ  PGC-1α signaling pathway, and enhance mitochondrial biogenesis. This should help people with mitochondrial disease and should be evident by increased exercise endurance and, in theory, improved cognitive function.

·        Telmisartan regulates the Bcl-2 cancer gene, implicated in autism

BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects

While the effect in autism is complex, Telmisartan is already seen as a potent target for prevention and treatment in human prostate cancer

·        Telmisartan and other ARBs appear to give protection from Alzheimer’s Disease (suggested to be via its effect on PPAR gamma). Perhaps useful for young adults with Down Syndrome, where early onset Alzheimer’s is expected?

·       Telmisartan and other ARBs have a tendency to increase the level of potassium in blood. Up to 10% of people would experience mild hyperkalemia.  For people with autism taking bumetanide, this effect on potassium might actually be helpful. They would need to reduce their potassium supplementation, or might need none at all.

Telmisartan in clinical trials related to autism

As is repeatedly the case, schizophrenia research is again more advanced than autism research. A quick check showed this:-

Telmisartan Completed Phase 4 Trials for Schizoaffective Disorders / Schizophrenia Treatment

This is a 12-week, randomized, double-blinded, placebo-controlled trial of telmisartan 80 mg/day as an adjunctive to clozapine or olanzapine therapy, in 70 schizophrenia subjects to examine telmisartan's effect on glucose metabolism, weight, food intake, resting energy expenditure, and body composition. In addition, the study will examine insulin's effects on psychopathology and cognition.

Conclusion

We currently have no possibility of something like Compound 21, but Telmisartan looks very interesting and it would nice if those psychiatrists who have trialed it in schizophrenia would do the same in autism.  

It looks like the beneficial effects should come at a lower dose than that used to lower blood pressure. In the schizophrenia trial I think they used a higher dose (80mg) than necessary, I suppose they wanted to maximize their chance of success.  In order to minimize any possible negative effects, I would suggest the psychiatrists trial 20mg in youth with autism.

There will be a post on PPAR delta and mitochondrial disease, because there are at least two other ways to target mitochondrial disease in this way, if you do not like Telmisartan.  There is the cheap drug Bezafibrate and the supplement berberine.