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NEUROPROTECTION

Overview of Neurodegenerative Diseases

Recent advances in understanding the biological processes of neuronal cell death as well as improved methods for demonstrating therapeutic effects in humans has led to the concept of pharmacological neurocytoprotection. Accordingly,  the search for drugs with a neuroprotective effect  has  now became an  active trend for neuronal diseases such as Parkinson's disease (PD),  Alzheimer's disease (AD),  Huntington's disease, amyotrophic lateral sclerosis or even multiple sclerosis. The two most common and classical examples of neurodegenerative diseases, AD and PD, are used here to highlight the scientific merits of our project.

AD is the most common form of senile dementia affecting millions of people worldwide (Alzheimer's Society). The neuropathological hallmarks of AD include excessive accumulation of abnormal tau filaments in neurofibrillary tangles, abundant deposits of β-amyloid in senile plaques, and extensive neuronal degeneration. Although the cause of the neuronal degeneration in AD is not known, recent studies revealed a possible link between neuronal apoptic cell death and increased β-amyloid production.  It has further been shown that oxidative stress is linked to β-amyloid-mediated neuronal cytotoxicity as it triggers and/or facilitates neurodegeneration through a wide range of molecular events which eventually lead to neuronal cell loss. Interestingly, antioxidants have recently been shown to  have a beneficial effect in neurodegenerative disorders, β-amyloid-induced neurotoxicity and oxidative stress in neuronal cells. Antioxidants may thus emerge as one of the therapeutic strategies to treat β-amyloid-induced neurotoxicity and improve neurological outcome in AD.

PD is a further example of typical neurodegenerative disorder and is characterised by symptoms including rest tremors, postural instability, gait abnormality, bradykinesia and rigidity (see Parkinson's Disease Society). The major pathological change of Parkinson's disease is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The nigral vulnerability fits well with the strong oxidative stress observed in PD. Excessive reactive oxygen species generation that is caused by increased oxidative damage and reduced antioxidant level has been identified within the degenerating substantia nigra of PD patients.  Interestingly, neurotoxins to dopaminergic neurons such as 6-hydroxydopamine (6-OHDA) which are routinely used to induce experimental Parkinsonism are known to induce the formation of free radicals, inflammatory processes and apoptosis. The toxicity of such Parkinson-inducing agents can also be altered by antioxidants.

Our Research Strategy

We  have already developed and used several in-house bioassay screens for the identification of  natural antioxidants. Our natural products have been demonstrated to possess potent protective effects against oxidative damage to biological molecules including DNA, as well as cytoprotection in a variety of experimental conditions [see under publication]. We are now further  studying the effect of our  natural antioxidant medicinal plants and their metabolites through  in vitro models of AD and PD. Our procedures utilise tissue culture-based  neurotoxicity/neuroprotective studies with biochemical endpoint measurements using   colourimetric, flouresence, flow cytometeric  and electrophoresis analysis. Our overall strategy is to identify a multifunctional drug candidate that works through one drug-multiple targets principle. For Alzheimer's disease, for example, our ideal candidate is  a neuroprotective agent that acts  through antioxidant mechanism,  overcomes the acetylcholine deficit through anticholinesterase effect and also  possesses antiamyloid properties.

Exemplary publication:

  • Roselli, M., Cavalluzzi, M.M., Bruno, C., Lovece, A., Carocci, A., Franchini, C., HABTEMARIAM, S., Lentini, G. (2016). Synthesis and evaluation of berberine derivatives and analogues as potential anti-acetylcholinesterase and antioxidant agents. Phytochemistry Letters 18, 150-156. Abstract

  • HABTEAMRIAM, S. (2016). The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer’s Disease. Evidence-Based Complementary and Alternative Medicine, Volume 2016 (2016), Article ID 2680409, 14 pages. Free Full Text Article

  • HABTEMARIAM, S. (2016). Rutin as a natural therapy for Alzheimer’s disease: Insights into its mechanisms of action. Current Medicinal Chemistry 23(9), 860-873. Abstract

  • Nabavi, S.F., HABTEMARIAM, S., Di Lorenzo, A., Sureda, A., Khanjani, S., Nabavi, S.M., Daglia, M. (2016). Post-stroke depression modulation and in vivo antioxidant activity of gallic acid and its synthetic derivatives in a murine model system. Nutrients 2016, 8(5), 248; doi:10.3390/nu8050248 (Open Access).

  • Nabavi, S.F., Braidy, N., HABTEMARIAM, S., Sureda, A., Manayi, A., Nabavi, S.M. (2016). Neuroprotective effects of fisetin in Alzheimer’s and Parkinson’s Diseases: From chemistry to medicine. Current Topics in Medicinal Chemistry,  16(17), 1910-1915.  Abstract

  • Nabavi, S.F., Braidy, N., Habtemariam, S., Orhan, I.E., Daglia, M., Manayi, A., Gortzi O., Nabavi, S.M. (2015). Neuroprotective effects of chrysin: From chemistry to medicine. Neurochemistry  International 90, 224-231. Abstract

  • Nabavi, S.M., HABTEMARIAM, S., Daglia, M., Loizzo, M.R., Tundis, R., Nabavi, S.F. (2015). Neuroprotective effects of ginkgolide B against ischemic stroke. Current Topics in Medicinal Chemistry 15(21), 2222-2232.   Abstract

  • Nabavi, S.F., Sureda, A., HABTEMARIAM, S., Nabavi, S.M. (2015). Ginkgolide Rd and ischemic stroke, a short review of literatures. Journal of Ginseng Research 39(4), 299-303.  Abstrac

  • Nabavi, S.F., Nabavi, S.M., HABTEMARIAM, S., Sureda, A., Moghaddam, A.H., Latifi, A.M. (2013). Neuroprotective effects of methyl-3-O-methyl gallate against sodium fluoride-induced oxidative stress in brain of rats. Cellular and Molecular Neurobiology 33(2), 261267.

  • HABTEMARIAM, S. (2011). The therapeutic potential of Berberis darwinii stem-bark: quantification of berberine and in vitro evidence for Alzheimer’s disease therapy. Natural Product Communications 6(8), 1089-1090.

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Dr Habtemariam BSc, MSc, PhD........FRSM, FRSC. .... With a Principal Lecturer post at Greenwich, Dr Habtemariam is a leader of the BSc Pharmaceutical Science programme and researches on bioassay & natural products-based drug development. ....More

 

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