Neuroscience
-
Neurotrophic factors (NTFs) are a relevant group of secreted proteins that modulate growth, differentiation, repair, and survival of neurons, playing a role in the maintenance of the synaptic unions, dendrites, and axons and also being crucial for peripheral nervous system development and regulating plasticity in the adult central nervous system. On the other hand, insulin-like growth factor 1 (IGF-1) has been ascertained multiple beneficial actions in the brain: neuro-development, -protection, -genesis and plasticity. ⋯ Results show that the mere IGF-1 deficiency seems to be responsible for an altered expression of genes coding for neurotrophic factors (particularly ciliary neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor), their receptors and signaling pathways (specially RET). The presented findings support that IGF-1 deficiency might be involved in the establishment and progression of neurodegenerative disorders.
-
Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet. ⋯ Additional functional assays were used to validate AQP4 inhibition and identified a promising structural series for medicinal chemistry. These efforts improved potency and revealed a compound we designated AER-270, N-[3,5-bis (trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. AER-270 and a prodrug with enhanced solubility, AER-271 2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, improved neurological outcome and reduced swelling in two models of CNS injury complicated by cerebral edema: water intoxication and ischemic stroke modeled by middle cerebral artery occlusion.
-
A significant level of genetic heterogeneity has been demonstrated in intellectual disability (ID). More than 700 genes have been identified in ID patients. To identify molecular pathways underlying this heterogeneity, we applied whole-transcriptome analysis using RNA-Seq in consanguineous families with ID. ⋯ FGFR2, but not SHTN1, was previously reported as an ID causing gene. Detailed gene ontology analyses identified pathways linked to tyrosine protein kinase, actin cytoskeleton, and axonogenesis to be affected in ID patients. The findings reported here provide new insights into the candidate genes and molecular pathways underling ID and highlight the key role of actin cytoskeleton in etiology of ID.
-
Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. ⋯ However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPIPSC and PPIPSS, but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults.