Our lead molecule, Neuroprotectin D1 (NPD1) is formed from DHA, the most abundant omega-3 fatty acid in the brain and it is normally present in the brain. Its formation is activated by neuronal growth factors and levels are increased during stress and injury as a protective mechanism.
Extensive pharmacological studies have confirmed that NPD1 broadly downregulates inflammation, including leukocyte migration, cytokine and chemokine secretion, and activation of Cox-2 and iNOS, without being immunosuppressive. Important in the control of the immune response is NPD1 activation of M2 macrophages to promote rapid clearance and restoration of tissue architecture. The CNS counterparts, M2 microglia, additionally exert trophic influence on neuron function and survival.
NPD1 protects cells in the affected host tissue from death by modulating levels of the bcl-2 family of proapoptotic proteins leading to reduced levels of Bax and Bad via up-regulation of bcl-2 and bcl-xL. NPD1 additionally promotes survival by upregulating the pAkt/mTor pathway, with promotion of tissue repair and neurite outgrowth. Survival benefit by NPD1 has been demonstrated in neurons, including motor neurons, and astrocytes exposed to oxidative stress or Abeta42 oligomers, and in cells transfected with ataxin-1 82Q or huntingtin.
NPD1 efficacy is evident in several in vivo models of relevance to neurological disease. In the Median Cerebral Artery Occlusion model loss of penumbral brain tissue was reduced by more than half and linked to improved function post-stroke. In experimental kindling epilepsy both spike frequency and amplitude were markedly attenuated. Following axotomy retinal ganglion neuron survival was several-fold higher in animals exposed to NPD1. Finally, in models of both inflammatory and neuropathic pain, NPD1 reduced pain by modulating neuronal plasticity without increasing the threshold for heat analgesia, indicating protection from changes that might lead to progressive chronic pain.
(in the scientific literature NPD1 is also referred to as Protectin D1; PD1)