NeuroNascent (United States)

Abstract BackgroundNNI‐362 is a novel small molecule identified by phenotypic screening to discover compounds that promote new neurons from human neural progenitor cells and have neuroprotective capacity. A placebo‐controlled, double‐blind Phase 1a trial examined the safety and tolerability of NNI‐362, as well as a pharmacodynamic outcome ‐ the level of plasma p‐tau181, a blood‐based biomarker specific to Alzheimer’s disease (AD) pathology. Results in animal models of other age‐related disorders suggest NNI‐362 has the potential to halt or reverse AD and PD clinically.MethodAn AAV‐alpha synuclein rat model of Parkinson’s disease (PD) (MOTAC, France) was used to examine the effects of NNI‐362 treatment. This model results in anosmia and motor phenotypes, loss of TH+ neurons, and diminished adult‐born neurons triggered by alpha‐synuclein expression in the SNpc. NNI‐362 and placebo were formulated as a lipid suspension and administered orally once daily for up to 6 weeks post‐stabilization of AAV‐synuclein expression. At 8 weeks, brains were removed, and the SNpc sectioned and stained for TH+ neurons, alpha‐synuclein, and BrdU+ adult‐born neurons. Results were compared to AAV‐GFP‐injected, vehicle‐treated rats ‐ in groups of M or F and treatment or placebo (n = 14/group, 7F/7M).ResultBrain permeable therapy NNI‐362 did not alter alpha‐synuclein levels, but promoted BrdU+ neurons in the substantia nigra. Thus, generating and protecting TH+ neurons was associated with reversing motor deficits in females. No motor deficits and no BrdU+ neuron deficits were observed in AAV alpha‐synuclein treated males (twice run model), as such no amelioration by NNI‐362 treatment.ConclusionOral NNI‐362 may be a cause‐agnostic therapeutic ‐ promoting region‐specific new neurons, TH+ neuronal protection, and behavioral improvement when induced by dopaminergic deficit, including neurogenesis deficit. After AAV‐alpha‐synuclein induction of 2 weeks, and then followed by chronic NNI‐362 treatment, both behavior and neuron numbers were no different than AAV‐GFP control levels in this clinically‐relevant experimental model of PD.

Abstract Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, we have developed a novel electrode that begins as an uncured, flowable pre-polymer that can be injected around a neuroanatomical target to minimize surgical manipulation. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, we performed detailed electrochemical and microscopy characterization of its material properties and validated the feasibility of using it to electrically stimulate the nervous system in rats and swine. The silicone-metal-particle composite performed very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of being simpler than traditional electrode designs, less invasive, and more cost-effective, the Injectrode has the potential to increase the adoption of neuromodulation therapies for existing and new indications.

Arctic ground squirrels (Urocitellus parryii, AGS) are unique in their ability to hibernate with a core body temperature near or below freezing. These animals also resist ischemic injury to the brain in vivo and oxygen-glucose deprivation in vitro. These unique qualities provided the impetus to isolate AGS neurons to examine inherent neuronal characteristics that could account for the capacity of AGS neurons to resist injury and cell death caused by ischemia and extremely cold temperatures. Identifying proteins or gene targets that allow for the distinctive properties of these cells could aid in the discovery of effective therapies for a number of ischemic indications and for the study of cold tolerance. Adult AGS hippocampus contains neural stem cells that continue to proliferate, allowing for easy expansion of these stem cells in culture. We describe here methods by which researchers can utilize these stem cells and differentiated neurons for any number of purposes. By closely following these steps the AGS neural stem cells can be expanded through two passages or more and then differentiated to a culture high in TUJ1-positive neurons (~50%) without utilizing toxic chemicals to minimize the number of dividing cells. Ischemia induces neurogenesis and neurogenesis which proceeds via MEK/ERK and PI3K/Akt survival signaling pathways contributes to ischemia resistance in vivo and in vitro (Kelleher-Anderson, Drew et al., in preparation). Further characterization of these unique neural cells can advance on many fronts, using some or all of these methods.