(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer’s disease challenged mice.

(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer’s disease challenged mice.

Publication date: Jul 08, 2019

Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.

Lecca, D., Bader, M., Tweedie, D., Hoffman, A.F., Jung, Y.J., Hsueh, S.C., Hoffer, B.J., Becker, R.E., Pick, C.G., Lupica, C.R., and Greig, N.H. (-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer’s disease challenged mice. 21542. 2019 Neurobiol Dis.

Concepts Keywords
Alzheimer Greater experimental groups
Astrocyte Control sham
Brain TBI
Cognitive Neuronal dysfunction
Cognitive Impairment Pro inflammatory cytokines
Cortex Cognitive impairment
Cytokine Branches of biology
Cytokines Organ systems
Dendritic Spines Alzheimer’s disease
GFAP Neurotrauma
Hippocampal Neurology
Hippocampi Glial cells
Hippocampus Amyloidosis
Immunohistochemical Concussion
Immunoreactivity Neuroinflammation
LTP PSEN1
Maze Phen
Mice
Microenvironment
MTBI
Neurodegeneration
Neurodegenerative Disorders
Neuropathologies
Parkinson
PSD
Risk Factor
Synaptic
Tartrate
TNF
Transgenic Mice
Traumatic Brain Injury

Semantics

Type Source Name
gene UNIPROT SYNM
gene UNIPROT FYN
gene UNIPROT PSD
gene UNIPROT PISD
gene UNIPROT FBXL15
gene UNIPROT GFAP
gene UNIPROT TNF
gene UNIPROT AIF1
disease MESH cognitive impairment
gene UNIPROT PSEN1
gene UNIPROT APP
gene UNIPROT BID
pathway BSID Release
disease MESH neurodegenerative disorders
disease MESH risk factor
pathway BSID Programmed Cell Death
drug DRUGBANK Phenserine

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *