Activation of migration of endogenous stem cells by erythropoietin as potential rescue for neurodegenerative diseases.

UNLABELLED: Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive cognitive dysfunction and memory loss. There is deposition of amyloid plaques in the brain and subsequent neuronal loss. Neuroinflammation plays a key role in the pathogenesis of AD. There is still no effective curative therapy for these patients. One promising strategy involves the stimulation of endogenous stem cells. This study investigated the therapeutic effect of erythropoietin (EPO) in neurogenesis, and proved its manipulation of the endogenous mesenchymal stem cells in model of lipopolysaccharide (LPS)-induced neuroinflammation. METHODS: Forty five adult male mice were divided equally into 3 groups: Group I (control), group II (LPS untreated group): mice were injected with single dose of lipopolysaccharide (LPS) 0.8 mg/kg intraperitoneally (ip) to induce neuroinflammation, group III (EPO treated group): in addition to (LPS) mice were further injected with EPO in dose of 40 µg/kg of body weight three times weekly for 5 consecutive weeks. Groups were tested for their locomotor activity and memory using open field test and Y-maze. Cerebral specimens were subjected to histological and morphometric studies. Glial fibrillary acidic protein (GFAP) and mesenchymal stem cell marker CD44 were assessed using immunostaining. Gene expression of brain derived neurotrophic factor (BDNF) was examined in brain tissue. RESULTS: LPS decreased locomotor activity and percentage of correct choices in Y-maze test. Cerebral sections of LPS treated mice showed increased percentage area of dark nuclei and amyloid plaques. Multiple GFAP positive astrocytes were detected in affected cerebral sections. In addition, decrease BDNF gene expression was noted. On the other hand, EPO treated group, showed improvement in locomotor and cognitive function. Examination of the cerebral sections showed multiple neurons exhibiting less dark nuclei and less amyloid plaques in comparison to the untreated group. GFAP positive astrocytes were also reduced. Cerebral sections of the EPO treated group showed multiple branched and spindle CD44 positive cells inside and around blood vessels more than in LPS group. This immunostaining was negative in the control group. EPO administration increased BDNF gene expression. CONCLUSION: This study proved that EPO provides excellent neuroprotective and neurotrophic effects in vivo model of LPS induced neuroinflammation. It enhances brain tissue regeneration via stimulation of endogenous mesenchymal stem cells proliferation and their migration to the site of inflammation. EPO also up regulates cerebral BDNF expression and production, which might contributes to EPO mediated neurogenesis. It also attenuates reactive gliosis thus reduces neuroinflammation. These encouraging results obtained with the use of EPO proved that it may be a promising candidate for future clinical application and treatment of neurodegenerative diseases.

The hematopoietic growth factor "erythropoietin" enhances the therapeutic effect of mesenchymal stem cells in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder clinically characterized by cognitive dysfunction and by deposition of amyloid plaques, neurofibrillary tangles in the brain. The study investigated the therapeutic effect of combined mesenchymal stem cells and erythropoietin on Alzheimer's disease. Five groups of mice were used: control group, Alzheimer's disease was induced in four groups by a single intraperitoneal injection of 0.8 mg kg(-1) lipopolysaccharide and divided as follows: Alzheimer's disease group, mesenchymal stem cells treated group by injecting mesenchymal stem cells into the tail vein (2 x 10(6) cells), erythropoietin treated group (40 microg kg(-1) b.wt.) injected intraperitoneally 3 times/week for 5 weeks and mesenchymal stem cells and erythropoietin treated group. Locomotor activity and memory were tested using open field and Y-maze. Histological, histochemical, immunohistochemical studies, morphometric measurements were examined in brain sections of all groups. Choline transferase activity, brain derived neurotrophic factor expression and mitochondrial swellings were assessed in cerebral specimens. Lipopolysaccharide decreased locomotor activity, memory, choline transferase activity and brain derived neurotrophic factor. It increased mitochondrial swelling, apoptotic index and amyloid deposition. Combined mesenchymal stem cells and erythropoietin markedly improved all these parameters. This study proved the effective role of mesenchymal stem cells in relieving Alzheimer's disease symptoms and manifestations; it highlighted the important role of erythropoietin in the treatment of Alzheimer's disease.