There are very few drugs to treat disease of the CNS, one reason for this is that they only target one aspect of the pathology when what is required are drugs that can modulate numerous pathways that are known to be involved in the pathology. Retinoic acid (RA) signalling is important for the maintenance and regeneration of central nervous system. The signalling pathway acts via the nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) of which there are three types of each and various subtypes. For signalling to occur a RAR/RXR heterodimer forms which binds at retinoic acid response elements (RARES) upstream of the target genes, RA binds and transcription occurs. It is thought that RA can regulate up to 20% of the genome. It is this regulation of numerous pathways that makes targeting of the RARS/RXRs an attractive drug option to treat CNS disease.
RA signalling is involved in repair of the injured brain, this includes spinal cord injury, stroke, and traumatic brain injury. RA signalling can also modulate the immune system and inflammation, which are believed to play a critical role in the development and progression of these diseases.
RA signalling have been shown to modulate various signalling pathways that are involved in the pathogenesis of neurodegenerative diseases, these are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and motoneuron disease (MND). RA signalling can inhibit the formation of amyloid beta (Aß) plaques, a hallmark of Alzheimer's disease, by regulating the expression of the amyloid precursor protein (APP) and its processing enzymes. In PD, the D1 and D2 receptors are regulated by RA signalling and protects dopaminergic neurons from degeneration by activating the nuclear receptor Nurr1. In HD, In Huntington's disease, retinoids have been shown to reduce the accumulation of mutant huntingtin protein, which is toxic to neurons. Retinoids can also enhance the clearance of mutant huntingtin protein by increasing the expression of heat shock proteins, which play a critical role in protein degradation. In MND, RA signalling has been implicated in neuronal cell survival.
The block in using retinoids as a therapeutic are their liabilities. Most notably are liver toxicity and skin irritation. The challenge is to synthesise receptor specific drugs that may overcome current toxicities and or target retinoids to the area of interest, using for example liposomes.
The aim of this collection of reviews and current research is to show the utility of using retinoids to treat CNS disorders and how they might progress into the clinic.
Topics to include
• Retinoid signalling in neurodegenerative diseases.
• Retinoids signalling in repair of the CNS, e.g. stroke, spinal cord injury, traumatic brain injury
• Retinoid signalling in neuronal development.
• Drug discovery for novel retinoids.
• Models of neurodegenerative disease using retinoids. In vivo, in vitro
• Pathway analysis in CNS disease using retinoids.
• Novel mechanisms to deliver retinoids to the CNS
• Current clinical overview of retinoids
There are very few drugs to treat disease of the CNS, one reason for this is that they only target one aspect of the pathology when what is required are drugs that can modulate numerous pathways that are known to be involved in the pathology. Retinoic acid (RA) signalling is important for the maintenance and regeneration of central nervous system. The signalling pathway acts via the nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) of which there are three types of each and various subtypes. For signalling to occur a RAR/RXR heterodimer forms which binds at retinoic acid response elements (RARES) upstream of the target genes, RA binds and transcription occurs. It is thought that RA can regulate up to 20% of the genome. It is this regulation of numerous pathways that makes targeting of the RARS/RXRs an attractive drug option to treat CNS disease.
RA signalling is involved in repair of the injured brain, this includes spinal cord injury, stroke, and traumatic brain injury. RA signalling can also modulate the immune system and inflammation, which are believed to play a critical role in the development and progression of these diseases.
RA signalling have been shown to modulate various signalling pathways that are involved in the pathogenesis of neurodegenerative diseases, these are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and motoneuron disease (MND). RA signalling can inhibit the formation of amyloid beta (Aß) plaques, a hallmark of Alzheimer's disease, by regulating the expression of the amyloid precursor protein (APP) and its processing enzymes. In PD, the D1 and D2 receptors are regulated by RA signalling and protects dopaminergic neurons from degeneration by activating the nuclear receptor Nurr1. In HD, In Huntington's disease, retinoids have been shown to reduce the accumulation of mutant huntingtin protein, which is toxic to neurons. Retinoids can also enhance the clearance of mutant huntingtin protein by increasing the expression of heat shock proteins, which play a critical role in protein degradation. In MND, RA signalling has been implicated in neuronal cell survival.
The block in using retinoids as a therapeutic are their liabilities. Most notably are liver toxicity and skin irritation. The challenge is to synthesise receptor specific drugs that may overcome current toxicities and or target retinoids to the area of interest, using for example liposomes.
The aim of this collection of reviews and current research is to show the utility of using retinoids to treat CNS disorders and how they might progress into the clinic.
Topics to include
• Retinoid signalling in neurodegenerative diseases.
• Retinoids signalling in repair of the CNS, e.g. stroke, spinal cord injury, traumatic brain injury
• Retinoid signalling in neuronal development.
• Drug discovery for novel retinoids.
• Models of neurodegenerative disease using retinoids. In vivo, in vitro
• Pathway analysis in CNS disease using retinoids.
• Novel mechanisms to deliver retinoids to the CNS
• Current clinical overview of retinoids
