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Neurodegenerative diseases pose a significant burden on individuals, families, and healthcare systems worldwide. One of the most promising avenues of research is the targeting of poly(ADP-ribose) polymerase-1 (PARP-1), a key enzyme involved in the pathogenesis of various neurodegenerative diseases. At Alfa Cytology, we provide PARP inhibitor development services for the neurodegenerative diseases therapy.
Upon activation, PARP-1 catalyzes the addition of poly(ADP-ribose) (PAR) chains to various target proteins, including histones, transcription factors, and DNA repair enzymes. However, in the context of neurodegenerative diseases, the overactivation of PARP-1 can lead to a detrimental cascade of events. Excessive PARP-1 activity results in the depletion of cellular NAD+, a crucial cofactor for energy metabolism and cell survival. This NAD+ depletion, coupled with the release of apoptosis-inducing factor (AIF) from the mitochondria, triggers a unique form of cell death called "parthanatos," which is characterized by large-scale DNA fragmentation and a caspase-independent mechanism of neuronal demise.
Fig. 1 Emerging role of PARP-1 in neurodegenerative diseases. (Thapa K., et al. 2021)
Researchers has conducted extensive preclinical studies, evaluating the neuroprotective potential of various PARP-1 inhibitors in animal models of neurodegenerative disorders. Their findings have demonstrated that the pharmacological inhibition of PARP-1 can effectively attenuate neuronal cell death, preserve cognitive and motor function, and slow the progression of disease in these models. By blocking the overactivation of PARP-1, we have been able to prevent the depletion of cellular NAD+, mitigate oxidative stress, and modulate key signaling pathways involved in neuroinflammation and apoptosis.
| Experimental Model | Disease Modelled | PARP Inhibitor | Effects |
| Cultured human neurons subjected to NMDA or oxygen/glucose deprivation | Neurodegeneration | Olaparib | Neuroprotection |
| Primary cortical neurons subjected to oxygen/glucose deprivation | Neurodegeneration | Veliparib | Neuroprotection and maintenance of NAD+ levels |
| Primary mouse cortical neurons subjected to α-synuclein | Neurodegenerative diseases | Veliparib, rucaparib or talazoparib | Protection against cell death |
| Intrastriatal injection of α-synuclein in mice | Neurodegeneration | Veliparib | Protection against dopaminergic neuron loss |
At Alfa Cytology, we offer a comprehensive range of preclinical contract research services to support the development of PARP-1 inhibitors for the treatment of neurodegenerative diseases. Our state-of-the-art facilities and highly experienced team of scientists provide expertise in various aspects of drug discovery and development.
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If you are interested in exploring the potential of PARP inhibitors for your research or drug development program, we invite you to contact our team of experts. Our experienced scientists are dedicated to providing tailored solutions and delivering high-quality data to support your research endeavors. To learn more about our services or to discuss a potential partnership, please contact us.
Reference
For research use only. Not intended for any clinical use.
