Wael M.Y. Mohamed

Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5×105 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.

Developing expertise in bioinformatics for biomedical research in Africa.

Research in bioinformatics has a central role in helping to advance biomedical research. However, its introduction to Africa has been met with some challenges (such as inadequate infrastructure, training opportunities, research funding, human resources, biorepositories and databases) that have contributed to the slow pace of development in this field across the continent. Fortunately, recent improvements in areas such as research funding, infrastructural support and capacity building are helping to develop bioinformatics into an important discipline in Africa. These contributions are leading to the establishment of world-class research facilities, biorepositories, training programmes, scientific networks and funding schemes to improve studies into disease and health in Africa. With increased contribution from all stakeholders, these developments could be further enhanced. Here, we discuss how the recent developments are contributing to the advancement of bioinformatics in Africa.

Mitochondrial complex I inhibition as a possible mechanism of chlorpyrifos induced neurotoxicity.

Background Organophosphates (OPs) represent the most widely used class of pesticides. Although perceived as low toxicity compounds compared to the previous organochlorines, they still possess neurotoxic effects both on acute and delayed levels. Delayed neurotoxic effects of OPs include OPIDN and OPICN. The mechanisms of these delayed effects have not been totally unraveled yet. One possible contributor for neurotoxicity is mitochondrial complex I (CI) inhibition. Purpose in the present study we evaluated the contributing role of (CI) inhibition in chlorpyrifos (CPF) induced delayed neuropathy in hens. Methods Experimented birds received 150 mg/kg of CPF, and evaluated behaviorally and biochemically. Results CPF treated hens received 150 mg/kg and developed signs of delayed neurotoxicity, which were verified by NTE inhibition. These effects were paralleled by CI inhibition and decrease in ATP level. Conclusions The data confirms the possible role of CI inhibition in CPF induced delayed neuropathy.

Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats

Aging related reduction in cerebral blood flow (CBF) has been linked with neurodegenerative disorders including Alzheimers disease and dementia. Experimentally, a condition of chronic cerebral hypoperfusion due to reduced CBF can be induced by permanent bilateral occlusion of common carotid arteries (2-vessel occlusion, 2VO) in rats. Since oxidative stress, leading to neuronal apoptosis and death, is one of the mechanisms, which is thought to play a significant role in chronic degenerative neurological disorders, the present study was planned to assess the ROS status by measuring the levels of anti-oxidant enzymes that might occur during chronic cerebral hypoperfusion. Antioxidant enzymes namely glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase were measured in the brain tissue at eight weeks of 2VO induction in rats. Results show significantly elevated levels of GPx, SOD, and catalase enzymes as compared with the control group. It is possible that compensatory rise in antioxidant enzymes occurs in response to increased oxidative stress following ischemic insult.

Developmental neurotoxic effects of Malathion on 3D neurosphere system

Developmental neurotoxicity (DNT) refers to the toxic effects induced by various chemicals on brain during the early childhood period. As human brains are vulnerable during this period, various chemicals would have significant effects on brains during early childhood. Some toxicants have been confirmed to induce developmental toxic effects on CNS; however, most of agents cannot be identified with certainty. This is because available animal models do not cover the whole spectrum of CNS developmental periods. A novel alternative method that can overcome most of the limitations of the conventional techniques is the use of 3D neurosphere system. This in-vitro system can recapitulate many of the changes during the period of brain development making it an ideal model for predicting developmental neurotoxic effects. In the present study we verified the possible DNT of Malathion, which is one of organophosphate pesticides with suggested possible neurotoxic effects on nursing children. Three doses of Malathion (0.25 μM, 1 μM and 10 μM) were used in cultured neurospheres for a period of 14 days. Malathion was found to affect proliferation, differentiation and viability of neurospheres, these effects were positively correlated to doses and time progress. This study confirms the DNT effects of Malathion on 3D neurosphere model. Further epidemiological studies will be needed to link these results to human exposure and effects data.

Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)

Abstract Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences from in vitro and in vivo disease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.

Tubulin and Tau: Possible targets for diagnosis of Parkinson’s and Alzheimer’s diseases

Neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by progressive neuronal loss and pathological accumulation of some proteins. Developing new biomarkers for both diseases is highly important for the early diagnosis and possible development of neuro-protective strategies. Serum antibodies (AIAs) against neuronal proteins are potential biomarkers for AD and PD that may be formed in response to their release into systemic circulation after brain damage. In the present study, two AIAs (tubulin and tau) were measured in sera of patients of PD and AD, compared to healthy controls. Results showed that both antibodies were elevated in patients with PD and AD compared to match controls. Curiously, the profile of elevation of antibodies was different in both diseases. In PD cases, tubulin and tau AIAs levels were similar. On the other hand, AD patients showed more elevation of tau AIAs compared to tubulin. Our current results suggested that AIAs panel could be able to identify cases with neuro-degeneration when compared with healthy subjects. More interestingly, it is possible to differentiate between PD and AD cases through identifying specific AIAs profile for each neurodegenerative states.

Corrigendum to: Genetic underpinnings in Alzheimer’s disease – a review

Corrigendum to: Ahmed A. Moustafa, Mubashir Hassan, Doaa H. Hewedi, Iman Hewedi, Julia K. Garami, Hany Al Ashwal, Nazar Zaki, Sung-Yum Seo, Vassilis Cutsuridis, Sergio L. Angulo, Joman Y. Natesh, Mohammad M. Herzallah, Dorota Frydecka, Błażej Misiak, Mohamed Salama, Wael Mohamed, Mohamad El Haj and Michael Hornberger. Genetic underpinnings in Alzheimer’s disease – a review. Reviews in the Neurosciences 2018; volume 29, Issue 1, pp. 21–38. (https://doi.org/10.1515/revneuro-2017-0036). In the author list of the above article the name of Joman Y. Natsheh was inadvertently misspelled as “Joman Y. Natesh”. In the following the author list with the correct spelling of J.Y. Natsheh’s name is given:

siRNA Blocking of Mammalian Target of Rapamycin (mTOR) Attenuates Pathology in Annonacin-Induced Tauopathy in Mice

Tauopathy is a pathological hallmark of many neurodegenerative diseases. It is characterized by abnormal aggregates of pathological phosphotau and somatodendritic redistribution. One suggested strategy for treating tauopathy is to stimulate autophagy, hence, getting rid of these pathological protein aggregates. One key controller of autophagy is mTOR. Since stimulation of mTOR leads to inhibition of autophagy, inhibitors of mTOR will cause stimulation of autophagy process. In this report, tauopathy was induced in mice using annonacin. Blocking of mTOR was achieved through stereotaxic injection of siRNA against mTOR. The behavioral and immunohistochemical evaluation revealed the development of tauopathy model as proven by deterioration of behavioral performance in open field test and significant tau aggregates in annonacin-treated mice. Blocking of mTOR revealed significant clearance of tau aggregates in the injected side; however, tau expression was not affected by mTOR blockage.

Light-Emitting Diode (LED) Therapy Attenuates Neurotoxicity of Methanol-Induced Memory Impairment and Apoptosis in The Hippocampus

BACKGROUND & OBJECTIVE The adolescent brain has a higher vulnerability to alcoholinduced neurotoxicity, compared to adults brain. Most studies have investigated the effect of ethanol consumption on the body, however, methanol consumption, which peaked in the last years, is still poorly explored. METHOD In this study, we investigated the effects of methanol neurotoxicity on memory function and pathological outcomes in the hippocampus of adolescent rats and examined the efficacy of Light- Emitting Diode (LED) therapy. Methanol induced neurotoxic rats showed a significant decrease in the latency period, in comparison to controls, which was significantly improved in LED treated rats at 7, 14 and 28 days, indicating recovery of memory function. In addition, methanol neurotoxicity in hippocampus caused a significant increase in cell death (caspase3+ cells) and cell edema at 7 and 28 days, which were significantly decreased by LED therapy. Furthermore, the number of glial fibrillary acid protein astrocytes was significantly lower in methanol rats, compared to controls, whereas LED treatment caused their significant increase. Finally, methanol neurotoxicity caused a significant decrease in the number of brain-derived neurotrophic factor (BDNF+) cells, but also circulating serum BDNF, at 7 and 28 days, compared to controls, which were significantly increased by LED therapy. Importantly, LED significantly increased the number of Ki-67+ cells and BDNF levels in the serum and hypothalamus in control-LED rats, compared to controls without LED therapy. CONCLUSION In conclusion, chronic methanol administration caused severe memory impairments and several pathological outcomes in the hippocampus of adolescent rats which were improved by LED therapy.