Nose-to-brain delivery of asarones for CNS conditions?

[Alchemica]

Nose-to-brain delivery of asarones for CNS conditions?

 

Ayurvedic medicine and traditional Chinese medicine (TCM) use Acorus preferably to treat central nervous system (CNS) related diseases such as epilepsy, insanity, mental weakness, or insomnia, Calamus has been widely used internally in both Chinese and Ayurvedic medicine for degenerative central nervous system disorders associated with communication, focus, memory and learning but there are concerns regarding the safety of such orally. 

 

The ability of asarones to induce such a broad range of neurotrophic factors (NGF, BDNF,  GDNF, CNTF in a dose-dependent manner), alongside other neuroprotective and neurorestorative pharmacological actions, intrigues me.

 

Pharmacologically, α- and β-asarone at lower doses (<50 mg/kg) exhibits a wide range of therapeutic activities such as antidepressant, antianxiety, anti-Alzheimer, and anti-Parkinson effects [1].

 

Asarones as a therapeutic are limited by poor absolute bioavailability when administered orally, less than 10%, because it is highly lipophilic and has poor solubility in water, coupled with extensive gastrointestinal and/or hepatic first-pass metabolism. 

 

There are concerns potentially harmful effects, such as genotoxicity particularly through accumulation in the liver where "both α- and β-asarone can cause hepatomas and might possess mutagenic, genotoxic, carcinogenic, and teratogenic effects". Because the amounts of asarone accumulated in liver may reflect its hepatotoxicity, there is special significance to reducing the amount of asarone in liver. 

 

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"The development of more efficient systems to deliver α- and β-asarone to their biological targets, particularly the brain, might allow for effective localized biological action while minimizing toxicity."

 

Efforts have been centred on exploring nose-to-brain delivery of asarones, particularly as nanoemulsions [1,2] In humans, 20mg asarone has been added to memantine for AD [3]

 

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"Drugs can travel from the olfactory epithelium in the nasal cavity straight into brain tissue via the olfactory bulb which gives intranasal administration special significance for brain diseases"

 

"...intranasal administration of asarone showed significant nose-to-brain transport, especially in the olfactory bulb, and such treatment yields equivalent or higher concentrations in other brain tissues compared to intravenous or oral administration"

I'm personally curious as to whether a simple spray of asarones emulsified in water with a polysorbate emulsifier, delivered via a nasal spray bottle may be simple enough to make a readily available nose-to-brain delivery system "polysorbates [are] a promising excipient to increase drug concentration in both plasma and brain via intranasal route".

 

The main beneficial actions of asarones, as described by [1], are summarised as:

 

" (1) antioxidant properties; (2) the regulation of various neuroprotective signaling pathways; (3) the reduction of aggregate formation and promotion of the clearance of pathogenic protein aggregates; (4) anti-inflammatory properties; (5) the inhibition of microglial activation; (6) the activation of NTFs-mediated neuroprotection; and (7) the modulation of neurotransmitter levels associated with behavioural functions and neuronal cell survival."

 

 
Actions of asarones on the CNS, taken from [1]

 

Normal vs diseased brain aspects

Asarone functions as a neuroprotective effect in both in vivo and in vitro models of neurodegeneration

 

- Enhance BDNF via TrkB and activate the ERK pathway, triggering antidepressant-like effects
- Significantly promoted the expression and secretion of neurotrophins, such as nerve growth factor (NGF), BDNF, and GDNF, in a dose-dependent manner. Also effects on CNTF 
- Maintain equilibrium between glutamate and GABA in the hippocampus, enhancing learning and memory abilities. β-asarone induced the high potentiation of GABAARs
-Anxiolytic effects of asarone were partially due to maintaining the balance between excitatory/inhibitory transmissions and attenuating neuronal hyper-excitability of excitatory neurons in the basolateral amygdala.
- modulates microglial morphological dynamics, may functionally relate to its influence on neurogenesis
- Other monoaminergic effects, particularly antidepressant effects mediated by noradrenergic (α1 and α2 adrenoceptors) and serotonergic (particularly, 5-HT1A receptors) systems.
- Enhances tyrosine hydroxylase activity with relevance to Parkinson's

 

My current line of thinking is to make an emulsion of a polysorbate emulsifier with calamus oil 1:1 in water and explore that. Any input appreciated.

 

 

1:1:2 Calamus EO:polysorbate solubiliser:saline administered by nasal spray has got quite a strong bit of burn to it but not totally intolerable.

 

Nasal sprays are normally less than 140uL/spray meaing at 25% EO concentration {assume 80% asarones), about 28mg asarone per spray may be possible. Even at that dose, each spray is quite painful but it may be feasible to - via multiple doses scattered through the day - reach a therapeutic dose of asarones intranasally with such.

References:
Balakrishnan, R.; Cho, D.-Y.; Kim, I.-S.; Seol, S.-H.; Choi, D.-K. Molecular Mechanisms and Therapeutic Potential of α- and β-Asarone in the Treatment of Neurological Disorders. Antioxidants 2022, 11, 281. https://doi.org/10.3390/antiox11020281 

Lu, J., Fu, T., Qian, Y., Zhang, Q., Zhu, H., Pan, L.,  Zhang, M. (2014). Distribution of α-asarone in brain following three different routes of administration in rats. European Journal of Pharmaceutical Sciences, 63, 63–70. . https://doi.org/10.3390/10.1016/j.ejps.2014.06.006

 

Pan L, Zhou J, Ju F, Zhu H. Intranasal delivery of α-asarone to the brain with lactoferrin-modified mPEG-PLA nanoparticles prepared by premix membrane emulsification. Drug Deliv Transl Res. 2018 Feb;8(1):83-96. doi: https://doi.org/10.1007/s13346-017-0438-8.

 Dong, Haiying; Wu, Shuqin; Hu, Nan; Xing, Guihua (2018) Efficacy of tenuigenin and β-asarone as augmentations for memantine in the treatment of Alzheimer’s disease https://doi.org/10.1097/WNR.0000000000000952

 

Edited December 19, 2023 by Alchemica

[Darklight]

OMG you are a legend and I adore you

 

I'd noticed some benefits with insufflation and LongCOV inflammation symptoms at a party last year, the details of which were sketchy af but the LongCOV inflammation reduction lingered for a few days well beyond the expected effects and I put that down to dopaminergic activity as anti-inflammatory as well as some expected minor anaesthesia ;) . Most of my remaining longCOV symptoms are nerve and cranial and when having a setback it feels like my nose and eyes are under pressure

 

On 09/12/2023 at 5:56 AM, Alchemica said:

My current line of thinking is to make an emulsion of a polysorbate emulsifier with calamus oil 1:1 in water and explore that. Any input appreciated.

 

I'd be interested to see how it goes. Or try some at 1/4 of the dose you recommend ( dilute bottle? ) as I respond strongly to BDNF enhancing compounds

 

Love your work there, you rock

[Alchemica]

Thanks for your input and kind words DL. Hope you get some improvement of your residual symptoms.

Initially there's not much robust acute improvement but symptoms were severe at baseline so not expecting quick results. If anything perhaps some destabilisation of mood etc but I sometimes feel that can be a part of the 'solve et coagula' of life. I particularly wonder if, as a significant portion of my symptoms was through an inhalation suicide attempt, this might be a very direct way to target the damaged pathways, particularly into the OFC, quite directly.

 

They did some research using aromatherapy for inhalant abuse, this is like the next level up, intranasal aromatherapy.

A novel approach of substitution therapy with inhalation of essential oil for the reduction of inhalant craving: A double-blinded randomized controlled trial

 

 

[Alchemica]

A few days in and perhaps the most robust change has been with potential anti-addictive activity, for me being able to say no to smoking which resurged recently and I wasn't able to get on top of (EDIT less sustained anti-addictive potential than I'd hoped). The regulation of neurotrophins, particularly GDNF [1], seems to have quite profound effects on addictive processes, the GDNF pathway implicated in the anti-addictive action of things like ibogaine. Some stability in mood developed over the extreme negative mood states and even some uplift, whilst still having profound motivational deficits and ability to initiate and maintain goal-directed activity. Been trying to have glimmers of sustained attention to focus on tasks like watching short bursts of movies or TV shows which is still incredibly challenging

 

As the administration via intranasal pathways directly into the olfactory bulb is likely to target the neurotrophic activity directly into the OFC and frontal lobes, it interests me how it could impact severe hypofrontality [2] particularly with regard to OFC functioning where damage can cause neurobehavioural issues

 

 

 

For a long time I've been walking around like a headless chook with aberrant motor functions, this seems to reduce the 'headless chook' wandering a bit

 

Edited December 17, 2023 by Alchemica

[fyzygy]

Sounds promising. I hope the positive effects increase over time. Would sub-lingual also work while avoiding toxic effects? Which Acorus species (and plant parts) have you been concentrating your efforts on? One plant that you sent me looks like a variegated sweet flag, I think you mentioned that it had been traditionally used among Japanese to treat stuttering? 

[Alchemica]

1 hour ago, fyzygy said:

Sounds promising. I hope the positive effects increase over time.Which Acorus species (and plant parts) have you been concentrating your efforts on? 

I'm just using a likely high asarone Acorus calamus essential oil. I don't want to make it a long-term addition but something to get out of a rut. Early days but small subjectively useful shifts, combined with little lifestyle shifts when I can seem to help slightly. I get very rigid in my routines and behaviours, so if this is a way to potentially plasticise my mind and behavioural repertoire a bit that could be good

 

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Would sub-lingual also work while avoiding toxic effects?

That could be useful and possibly minimise toxicity? I know some people simply chew the calamus rhizome, that seems to be the suggested way to use the Japanese Sweet Flag SAB sells for stimulant effects. This intranasal spray is a bit more full on with quite significant levels of asarone which I think would be hard to reach via plain herb
 

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Variegated sweet flag, I think you mentioned that it had been traditionally used among Japanese to treat stuttering? 

 

Yeah that one's Acorus gramineus, it's got a diverse range of constituents that have interesting pharmacology aside from asarones. Still, whilst it seems to have quite prominent TCM use etc, I'd probably stick with chewing it etc as you mention

My notes on A. gramineus
 

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Acorus gramineus is a traditional medicine used to treat various disorders including cognitive disorders where of all the traditional Chinese medicines used in treating cognitive disorders, the rhizome appears with the highest frequency. In TCM it has an action of "calming heart and inducing tranquilisation"
 

It contains β-asarone, α-asarone and other phenylpropenes as well as lignans, along with aporphine-type alkaloids with the essential oil having NMDA receptor antagonist-like action and possibly increases NE, DA and 5-HT, also decreasing the activity of acetylcholinesterase. A water extract demonstrated specific binding to striatal dopamine D1 and D2 receptors and competed with [3H]muscimol for specific binding to the GABA binding site of cortex GABAA receptor

 

 

 

[Alchemica]

Stuck with this for awhile and there's been the slow but gradual return of some seemingly simple cognitive functions when used catalytically with effort and attempting to retrain my mind.

For example, I was unable to sit and watch something as simple as a short youtube clip and follow the video. I've lately got back into watching inspirational short videos that I'm enjoying and can now watch something like a 30min clip which was previously totally unfeasible. I've started to embrace the need to do a lot more simple cognitive remediation in my day, for example getting back into colouring in an adult colouring books etc as an activity

 

It hasn't all been linear for recovering some levels of very basic functionality, the cognitive fatigue associated with essentially retraining and forging some new connections of some basic cognitive functions has been extreme and literally left me floored and sometimes come at the expense of maintaining functionality in other domains.