Nose-to-brain delivery of asarones for CNS conditions? While 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. 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. "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] "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 signalling 1 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] 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 2 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 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 3