Jonathan Corcoran ^1* Jörg Mey ²

• ¹ King's College London, London, United Kingdom
• ² Hospital Nacional de Parapléjicos, Toledo, Spain

Whilst originally regarded as a nuclear signalling, it is now recognised that RA can exert important functions through non-canonical pathways. Piazza et al, Frontiers | Non-canonical retinoid signaling in neural development, regeneration and synaptic function (frontiersin.org) review these in depth and discuss their importance in activating protein kinase C (PKC), PI3K/AKT3 and ERK1/2 signalling in neural development, nerve regeneration and synapse formation. As these pathways are highly relevant clinically, synthetic retinoids have been developed that induce axonal regeneration by activating genomic (RAR/RXR) and non-genomic (ERK1/2 kinase) pathways (Khatib et al., 2019).Despite the multitude of regenerative pathways governed by RA signalling, all-trans RA itself is not an attractive CNS therapeutic. Not only does it have poor drug-like properties, is associated with liver toxicity, and is rapidly catabolised by CYP26 enzymes, but it is also a pan-RAR agonist. Since these receptors are widely expressed, undesirable effects, both inside and outside of the CNS, are likely to occur at pharmacological doses. In addition, the spatiotemporal fine-tunning of activation of specific RARs in repair mechanisms, such as in spinal cord regeneration for instance, where coordination of RAR and  is required, cannot be achieved with RA (Goncalves et al., 2019b). The challenge is to synthesise receptor specific drugs that overcome current toxicities (Borthwick et al., 2020) and or target retinoids to the area of interest, using for example liposomes (Ferreira et al., 2020).To date there are only six retinoids that have entered the clinic, these are pan-RARs (tretinoin, a gel formulation, isotretinoin, oral formulation) (Baldwin et al.;Layton, 2009) and a RAR/ agonist (adapalene, a gel formulation) for treatment of acne (Rusu et al., 2020), one is a RAR/ agonist (tamibarotene), for the treatment of acute promyelocytic leukaemia (Nagai and Ambinder, 2023), and an RXR agonist (bexarotene) for cutaneous T cell lymphoma (Scarisbrick et al., 2013).Recent work has developed a RAR selective agonist, C286, which is less lipophilic than current clinical retinoids, does not have their typical liabilities, has good oral availability and can cross the blood brain barrier (Goncalves et al., 2019a).The paper by Goncalves et al, Frontiers | C286 an orally available retinoic acid receptor  agonist drug regulates multiple pathways to achieve spinal cord injury repair (frontiersin.org) further validates the use of C286 to stimulate axonal/neurite outgrowth and highlights the numerous pathways it regulates to achieve that effect. These pathways are involved in synaptogenesis, axonal outgrowth and modulation of the extracellular matrix. and are present in different rodent models of nerve injury, and across species, human derived neurons significantly increased neurite outgrowth in response to C286 treatment. This is important as it suggests that RARb signalling through C286 evokes the same reparative mechanisms in different nerve injuries and in different species, thus being predictive of successful efficacy in humans. The dose used in the proof-of-concept studies (POC) does not exceed the no -observedadverse -effect level (NOAEL) and use of clinical retinoids which are not RARb selective do not give a functional output in nerve injury. Taken together the data suggests that P IIA trials are merited in acute nerve injuries and given the cross over in pathways with chronic CNS injury the drug may be of use here too.With regards to RXR signalling, given the difficulty in developing specific agonists with a good safety profile, a possible approach is to target the orphan nuclear receptor they partner with. For instance, Magan et al, Frontiers | Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System (frontiersin.org) show that the farnesoid X receptor (FXR) is expressed in the hypothalamus and is involved in energy homeostasis. They activate the FXR/RXR with FXR agonist GW4064 so negating the use of an RXR agonist such as bexarotene and therefore a more specific outcome is achieved. The delivery of the agonist is done by intracerebroventricular (ICV) treatment to avoid activating peripheral FXR. Similarly, Zhang et al, Frontiers | Regulation of nuclear factor erythroid-2-related factor 2 as a potential therapeutic target in intracerebral hemorrhage (frontiersin.org) review the role of Nuclear factor erythroid-2-related factor 2 (Nrf2) in preventing oxidative stress in stroke and therefore mitigating brain injury. There are a number of pathways discussed that can increase the expression of NrF2, and one of these is nuclear orphan receptor, Peroxisome proliferator-activated receptor γ (PPARγ). Agonists of PPAR include thiazolidinediones which are used to treat diabetes mellitus although as with current FXR agonists they need to be developed for better brain penetration to treat CNS disease and or a better delivery mechanism.In conclusion, the research topic has brought new pathways involved in CNS repair that are under the regulation of the retinoid signalling. This provides a fertile platform for further target validation and translational research studies to pave the way for novel therapeutic developments for a wide umbrella of neurodegenerative diseases.