Therapeutic approaches to counteract inflammation of Central Nervous System: role of SUN11602 in brain trauma and Parkinson's disease and DdPAC light stimulation for Alzheimer's disease

The Central Nervous System (CNS) is an important control centre of the total human body and with complex formation and for this reason is particularly susceptible to disorders, which today represent pathological conditions affecting more than a billion people in the world. One most common CNS disorders is represented by Traumatic Brain Injury (TBI), like an external mechanical force, such as falls, vehicle accidents and sports injuries, causing damage to the brain. Head trauma triggers a cascade of events, starting from microglia activation and the formation of astrocytes reactive, that activate several signalling pathways involved in inflammation of the CNS, named neuroinflammation. The main pathways include NF-B, MAPK, JACK/STAT/SOCS pathways and others, leading neurons towards apoptotic way through the involvement of the Bcl2/Bax signalling pathway. Numerous cohort studies of clinical research demonstrated that neuroinflammation generated by TBI represents an important predictive factor for the development of neurodegenerative diseases (NDDs), which are the most common causes of death worldwide in people over 60 years of age. They are characterized by a progressive neuron deterioration that affects different brain regions. The most well-known include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). The etiopathogenesis of neurodegenerative diseases is multifactorial and, nowadays, the triggering cause of these diseases is not entirely clear. PD and AD are among the most frequent NDDs, and their development is thought to be based on an inflammatory process involving the CNS, named neuroinflammation, which involves specific cells of the CNS, such as astrocytes and microglia, modulating the inflammatory processes. Moreover, in this context, there is a dysregulation of cyclic Adenosine monophosphate (cAMP) signalling, an important second messenger, that plays a pivotal role in the CNS in physiological conditions. Great strides have been made in research to seek new therapeutic opportunities for PD and AD. Here, we focused on both pharmacological, based on the use of bFGF, and optogenetic approaches, based on photoactivable adenylate cyclases (PAC). Firstly, bFGF exerts neuroprotective effects in the CNS-damaged supporting neuronal survival, counteracting the neuroinflammation and apoptotic process, contributing to neuronal death, and repairing damaged tissues. Therefore, a new mimic of bFGF, SUN11602, has been synthesized. It has been demonstrated that SUN11602 interacts with the FGFR1 receptor similarly to bFGF, thus enhancing its phosphorylation and stimulating neuronal growth and survival in pathological conditions. SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory and reducing nigrostriatal degeneration. Secondly, another novel approach is represented by an optogenetic model using PAC. Especially in this study, we used a variant of the Deinococcus deserti bacteriophytochrome (BphP), DdPAC, that can increase cAMP levels under red light stimuli ( 685 nm), providing insights into the role of cAMP increases in various neuronal processes, such as the study of neuroplasticity. To study cAMP signalling, an Adeno-Associated Virus (AAV) construct was built, containing DdPAC under neuronal or astrocyte-specific promoters, and was injected directly into the hippocampus area of WT and the 5xFAD Alzheimer mouse model. The DdPAC stimulation, of the WT and 5xFAD mice, reduced the GFAP expression, a marker of astrogliosis, and beta-Amyloid (A-beta) deposition and the number of A-beta plaques in the hippocampus when DdPAC was stimulated specifically in astrocytes, while minor effects were observed when DdPAC was stimulated in neurons, suggesting that cAMP increases in astrocyte might be a better therapeutic opportunity for AD. In conclusion, the results obtained by both approaches, pharmacological with SUN11602 and optogenetic by DdPAC stimulation specifically in astrocytes may offer promising therapeutic opportunities for NDDs.