In the proposed project, we will study the role of mast cells in inflammation leading to brain injury and consequently to mental and neurological disorders after neonatal hemorrhagic stroke, specifically germinal matrix hemorrhage (GMH). Most importantly, we will test whether stabilization of mast cells after GMH will attenuate GMH-induced brain injury and improve mental and neurological functions. GMH is a devastating disease affecting over 12,000 premature infants annually, resulting in hydrocephalus and cerebral palsy, leading to mental retardation and lifelong disabilities. GMH, occurs in nearly half of low birth weight infants, significantly increases risk of depressive and obsessive-compulsive disorders. Additionally, GMH-induced parenchymal lesions and ventricular enlargement increases the risk of attention deficit and hyperactivity disorder. GMH patients who survive without disability will have significantly higher risk of developing attention deficit, anxiety, and mood disorder. GMH induced cerebral ventricular enlargement is a strong and significant risk factor for the development of autism spectrum disorders and schizophrenia. We recently developed a GMH model in neonatal rats and the neurological sequelae observed in this animal model were similar to that seen in human preterm neonates clinically. In the GMH pups, we observed a significant delay in development, which resulted in the loss of `working' memory' (evaluated by T-Maze test), impaired spatial learning (Water Maze test), and hyperactivity (Open Field test) as well as in motor dysfunctions during the juvenile development stage. In this model, we demonstrated that TGF?1 accumulation and the activation of the TGF? pathway significantly contributed to brain injury after GMH. However the source of active TGF?1 in this model remains unclear.
In Aim 1 of the proposed project, we will determine if mast cells are a major player in GMH- induced TGF? pathway activation. Most importantly we will determine if mast cell stabilization will decrease GMH-induced brain injury and improve mental functions. In additional to tests mentioned above, recording observations of repetitive stereotypic movements will provide measures of autism-like and/or obsessive compulsive behaviors. Affective behaviors, including anxiety and risk-taking behaviors, will be assessed with the zero maze, and depression/learned-helplessness-like behaviors will be measured using the forced swim, and sucrose preference tests. Finally, social dominance, approach, and scent marking will be measured by recording observations associated with exposure to novel females and males. For mast cell stabilization we will use 1) Omalizumab, the drug clinically approved for treating the diseases related to pathologic mast cell activation in humans and 2) Hydrogen inhalation, a safe treatment without reported side effects.
In Aim 2, we will study the mechanism of mast cell stabilization-induced brain protection. We hypothesize that inhibition of mast cell mediators will attenuate TGF? activation thus decrease brain inflammation via downregulation of IL- 17, resulting in the attenuation of brain injury and neurological deficits after GMH.
Infants with germinal matrix hemorrhage are at risk of post-hemorrhagic hydrocephalus and cerebral palsy. Since preterm birth rates and their survival have considerably increased over the past two decades, germinal matrix hemorrhage is a serious socio-economic problem. This study will investigate the role of mast cells in neuroinflammation after germinal matrix hemorrhage and examine mast cell stabilization as a therapy to improve the life quality of germinal matrix hemorrhage patients.
| Eser Ocak, Pinar; Ocak, Umut; Sherchan, Prativa et al. (2018) Insights into major facilitator superfamily domain-containing protein-2a (Mfsd2a) in physiology and pathophysiology. What do we know so far? J Neurosci Res : |
