An extremely simple question. WHOM IS GOING TO DO FOLLOWUP TO SEE IF THIS CAN GET ACROSS THE BLOOD BRAIN BARRIER? NO ONE? YOU'RE SCREWED. Deal with the incompetence of the stroke medical world, they have no clue what needs to be done until they are the 1 in 4 per WHO that has a stroke? Will that finally get you to do your job properly? Of course you will be disabled by then and lose your job so schadenfreude to you.
In vitro is used to describe work that's performed outside of a living organism. Or do we get around this problem by just increasing nitric oxide? WHOM WILL ANSWER THAT FUCKINGLY SIMPLE QUESTION?
Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide
- 1Department of Cell Biology, Physiology and Immunology, Faculty of Biology and Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- 2Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain
- 3Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- 4Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), University of Queensland, St Lucia Campus, Brisbane, QLD, Australia
Introduction
Mammalian adult Central Nervous System (CNS) differs
from embryonic CNS and Peripheral Nervous System (PNS) by their inherent
ability to regenerate lesioned tissues. After axotomy, the first
regeneration step requires the formation of a functional growth cone.
Unfortunately, the adult CNS has a reduced capacity to form new growth
cones due, to the existence of intrinsic factors (Ertürk et al., 2007) and the presence of growth-inhibitory molecules (Tan et al., 2005; Li et al., 2013).
After axotomy, organized sequential steps are required to form new and
functional growth cones. The first of which consists of the influx of
calcium, which increases exocytosis to fuse additional membrane to form a
sealing patch to repair the ablated axon (Bradke et al., 2012; Blanquie and Bradke, 2018; Curcio and Bradke, 2018).
Following this initial membrane addition, microtubule and actin
cytoskeleton is reorganized, multiple signaling cascades are activated
and the new membrane is transported to the tip of the growing axon (Bradke et al., 2012; He and Jin, 2016; Curcio and Bradke, 2018).
A tight control of the actin cytoskeleton is crucial for the formation
and functionality of the new growth cone. Regulation of actin requires
the initiation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling
cascade (Henle et al., 2011; Kakumoto and Nakata, 2013; Berry et al., 2016; Curcio and Bradke, 2018; Jin et al., 2018).
Akt phosphorylation induces the activation of nitric oxide synthase
(NOS), whose function is associated with actin reorganization and cell
survival (Michell et al., 1999; Van Wagenen and Rehder, 2001; Welshhans and Rehder, 2005; Cooke et al., 2013; Sild et al., 2016). NOS produces nitric oxide (NO), a gaseous molecule involved in neurotransmission, neuronal growth and filopodia formation (Van Wagenen and Rehder, 2001; Welshhans and Rehder, 2005; Tojima et al., 2009; Forstermann and Sessa, 2012). NO is also associated with axon regeneration in insect neurons (Stern and Bicker, 2008) and the snail Helisoma trivolvis (Cooke et al., 2013). NO cannot be stored in cells, so its effects depend on the de novo
synthesis by NOS activity. From the three types of NOS, neural NOS
(nNOS) is synthesized in CNS and PNS neurons and its activity is
regulated by intracellular calcium levels. The NO downstream signaling
pathway involves the activation of protein kinase G (PKG) and
actin-associated proteins such as the Enabled/vasodilator-stimulated
phosphoprotein (Ena/VASP), resulting in a strong reorganization of the
actin cytoskeleton (Zhou and Zhu, 2009; Forstermann and Sessa, 2012; Cossenza et al., 2014).
Nystatin is a drug commonly used as an antifungal agent
because of its ability to destabilize fungal membranes by binding and
extracting ergosterol, causing changes in cell permeability and,
eventually, cell lysis (Bolard, 1986; Coutinho et al., 2004).
Nystatin can also bind to cholesterol and extract this lipid from the
membranes of mammalian cells. As a consequence, Nystatin has been widely
used to disrupt and study the cellular function of lipid rafts. Lipid
rafts are membrane microdomains enriched in cholesterol and
sphingolipids, that facilitate the compartmentalization of signaling
proteins, working as platforms for spatial and temporal regulation of
the cytoskeleton, membrane anchoring, and cell adhesion, controlling the
motility of growth cones (Guirland and Zheng, 2007), and the regenerative properties of lesioned axons (Tassew et al., 2014; Roselló-Busquets et al., 2019).
The extended clinical use of Nystatin, together with its ability to
affect the organization of lipid rafts, makes it an ideal candidate to
explore its function as a possible therapeutic agent for the treatment
of spinal cord lesions.
Here, we performed an in vitro evaluation of the
Nystatin induced axonal regenerative properties, analyzing the effect of
various concentrations and incubation times of this compound in
hippocampal neurons. The study of the downstream signaling proteins
responsible for the observed effects of Nystatin suggested that Nystatin
differentially activates Akt phosphorylation and NO production in a
concentration-dependent manner. We propose Nystatin as a novel neuronal
pharmacological regulator of Akt and nNOS activity that modifies growth
cone dynamics and promotes axonal regeneration post-axotomy.
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