Objective/Rationale:
Chronic inflammation mediated by microglial cells is the fundamental process contributing to the death of dopamine producing neurons in the brain. Production of inflammatory products by these microglial cells characterizes the slow destructive process in Parkinson’s disease. NF-κB is a protein which controls the expression of over 200 genes critical in inflammation and the immune response within the microglial cell, and we believe that therapies aimed at inhibiting the expression of NF-kB will be successful in reversing or slowing the progression of Parkinson’s disease.
Project Description:
Our company has developed two compounds which significantly inhibit the activation of NF-kB both in culture and in animal models of chronic inflammation. We propose to develop a novel therapy for PD by targeting microglia-mediated inflammation as both a preventative and a therapeutical approach to PD. In this project, we will use our anti-NF-kB compounds in an animal model of PD to investigate the effects of administering different doses at different times on the cellular, molecular, and behavioral progression of PD over time. We will then assess whether blocking inflammation reverses destruction of dopamine producing neurons, and actually leads to regeneration of these cells within the brain, to determine the most effective dose and timing of therapeutic intervention. We anticipate that these treatments will not only halt the progression of PD, but also lead to significant reversal of neurodegeneration and improvement in the physical/behavioral abnormalities of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Any successful therapy to reverse the progression of Parkinson’s disease must stop the root cause of the disease, which is the slow neurodegenerative inflammatory process mediated by microglial cells within the area of the brain containing the dopamine-producing neurons. Our approach is to inhibit the central control mechanism of inflammation, the protein NF-kB, which controls the production of numerous inflammatory products by microglial cells which participate in the destruction of dopamine-producing neurons. One or both of these two compounds hold the potential to immediately stop or even reverse the degenerative effects of PD and, combined with other neuron-restorative therapies, to provide an effective treatment for PD.
Anticipated Outcome:
We anticipate that one or both of our compounds will be effective at inhibiting the production of inflammatory mediators by microglial cells in the central nervous system. This will stop the neurodegenerative process in PD, and may even lead to the reversal of neuronal destruction within the brain. Animals treated with these compounds will not show a reduction in dopamine-producing neurons, and will show no molecular or behavioral changes normally associated with progressive PD.
Final Outcome
Inflammatory responses by microglial cells within the substantia nigra (SN) are a key part of the etiology of . Parkinson's disease. NF-kappaB is the key transcriptional factor expressed in microglia that controls the quality and quantity of their response to activation signals, and has been postulated to play a central role in the destruction of DA neurons by this microglial-mediated inflammatory response. Theralogics, Inc. has tested a small molecule therapeutic (TLX200 1) directed against IKKbetar a key enzyme in the pathway that leads to the activation of NFkB, for its efficacy in inhibiting inflammation induced toxicity of dopamine-producing neurons within the SN. We found that administration of TLX2001 inhibited the activation of microglia induced by nigral injection of lipopolysaccharide (LPS) and significantly attenuated LPS-induced loss of DA neurons in the SN. Mechanistic studies revealed that neuroprotective effects of TLX2001 were mediated by suppressing the activity of microglial NADPH oxidase and decreasing the production of reactive oxygen species, as well as by inhibiting NF-kappaB-mediated gene transcription of various proinflammatory mediators in microglia via IKK-beta suppression. These findings indicate that TLX2001 afforded potent neuroprotection against LPS-induced neurodegeneration through selective inhibition of NF-kappaB activation and may be of potential benefit in the treatment of PD.