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Effects of Noopept on Alzheimer’s Symptoms 1 Effects of Noopept on Alzheimer’s Symptoms By Emilie Koetter Effects of Noopept on Alzheimer’s Symptoms 2 Introduction Alzheimer’s disease, a progressive form of dementia, causes a decline in mental ability which includes memory, thinking, perception, language, and can even affect personality. The exact cause of Alzheimer’s disease is not yet known, but studies have shown that an array of events occurring in the brain over a vast period of time lead to its evolution. The main precursor leading to Alzheimer’s disease is the aggregation of Amyloid Beta protein (ABeta peptide) which forms senile plaques and neurofibrillary tangles in brain tissue. Senile plaques and neurofibrillary tangles are thought to cause cholinergic deficit which results in memory deterioration indicative of Alzheimer’s Disease (Ostrovskaya et. al, 2006). Alzheimer’s is the sixth leading cause of death in the United States and currently has no known cure, method of prevention, or way to slow its progression (Ostrovskaya et. al, 2006). In Georgia alone nearly 120,000 people over the age of 65 have been diagnosed with Alzheimer’s disease. Many studies have explored the possible effects of a class of nutrient-based cognitive enhancers called nootropics on mental ability and memory-retention in Alzheimer’s patients. Nootropics can be found as supplements, drugs, functional foods, and nutraceuticals. Interest in the effects of cognitive enhancers, especially nootropics, has recently increased dramatically due to their memory enhancing and neuroprotective properties (Ostrovskaya et. al, 2006). My interest in this topic stems from a desire to preventing onset of Alzheimer’s in family members who are at high risk for developing this disease. My primary source is by Ostrovskaya et. al and focuses on improvement of cognitive function in mice with Alzheimer-like symptoms and hypothesizes that these agents will improve spatial memory and enhance immune response to prefibril bodies. The primary focus of this paper is to evaluate the effectiveness of the nootropic noopept (N-phenylacetyl-L-prolylglycine Effects of Noopept on Alzheimer’s Symptoms 3 ethyl ester) on improving Alzheimer’s symptoms (Ostrovskaya et. al, 2006). Considering the available research, I hypothesize that noopept may be a gateway to finding a suitable treatment for the cognitive deficits associated with neurodegenerative diseases, specifically Alzheimer’s disease. Methods Two groups consisting of sixteen male NMRI (National Medical Research Institute) mice per group were designated for experimentation. Chosen mice fit a specific weight and age for standardization. This mouse strain was chosen because it exhibits similar immunosuppression to that found in Alzheimer’s patients. Olfactory bulbectomy operations were performed on one group of mice which was designated OB (olfactory bulbectomy). Removal of the olfactory bulbs in mice has been shown to produce Alzheimer-like behavior as well as biochemical and physiological similarities in the brain. Mice in the second group underwent sham operations and were designated SO (sham operated). The sham operation consisted of drilling a 2 mm hole above the olfactory bulbs without removal of the structures (Ostrovskaya et. al, 2006). After surgery, each group was randomly divided into two additional subgroups. One OB and one SO subgroup received 0.01mg/kg noopept (NP) per day for 21 consecutive days (OB+NP and SO+NP). The remaining groups were administered 0.9% saline for 21 days (OB+saline and SO+saline). Simultaneous to beginning treatment the mice also began training in a Morris Water Maze created to teach and assess spatial orientation and memory. The maze was divided into four quadrants and contained an underwater platform in quadrant 3 for the duration of training. The tank was filled with water which was clouded by powdered milk to make the platform invisible to the swimming mice (Ostrovskaya et. al, 2006). Effects of Noopept on Alzheimer’s Symptoms 4 Upon training completion each mouse was tested on learning ability and spatial memory. Learning ability was measured based on the amount of time taken to reach the platform. After removing the platform from the tank a separate test was administered to evaluate spatial memory. Determinants included the amount of time spent in each quadrant and the number of times each quadrant was entered (Ostrovskaya et. al, 2006). A link has been determined between amyloid structure aggregates in the brain and the onset of Alzheimer’s disease. Another goal of this study is to analyze the immunity response to ABeta peptide, equine lysozyme, and S100b. ABeta peptide was synthesized by the Yu. A. Ovchinnikov Institute of Bioorganic Chemistry RAS for use in this study (Ostrovskaya et. al, 2006). Equine lysozyme is a calcium-binding protein generally found throughout the human body and functions as a protein precursor to C-type lysozyme. In Alzheimer’s patients, cerebral serous fluid is devoid of equine lysozyme (Casaite et. al, 2009). This protein was purchased from Sigma, USA to be used in this study. S100b is also a calcium-binding protein implicated in neurodegenerative diseases. S100b is involved in regulation of neuronal survival. S100b is produced by astrocytes in the central nervous system and is found at higher levels when damage has occurred in the nervous system (Hauschild et. al, 1999). Immunity to amyloid structures was determined based on the level of antibodies to ABeta peptide, equine lysozyme, and S100b in the blood serum using solid phase ELISA (enzymelinked immunosorbent assay). ELISA is an experimental method used to determine the presence of a substance within a liquid sample. A Student’s t-test was employed to evaluate ELISA results for immunity while ANOVA (analysis of variance) was used to determine the variation in means for spatial memory and orientation testing. ANOVA also utilizes the t-test. P values were then used to evaluate significance of data for each group (Ostrovskaya et. al, 2006). Effects of Noopept on Alzheimer’s Symptoms 5 Results All groups displayed a decrease in the time taken to locate the hidden platform during training (p=0.000001). No difference in the rate of learning was found between groups. When the hidden platform was removed from the maze during spatial memory testing, a significant correlation was found between group and quadrant. This correlation was indicated by both criterion, quadrant occupancy time and the number of entries into each quadrant. Each group searched for the hidden platform except for OB+saline. OB+saline showed no preference for any quadrant. The remaining groups (OB+NP, SO+NP, and SO+saline) showed a preference for quadrant 3 which contained the target platform during training. Both OB+NP and SO+NP groups showed higher occupancy times in quadrant 3 compared to both groups treated with saline, as well as a higher number of entries into quadrant 3. These result indicate impaired spatial memory in OB+saline mice following olfactory bulbectomy and an increase in consistency following treatment of noopept (Ostrovskaya et. al, 2006). This study also evaluated the immunity of NMRI mice to ABeta peptide, equine lysozyme, and S100b. ELISA was employed to measure the autoimmune response to ABeta peptide. SO and OB mice treated with saline had low levels of antibodies to ABeta structures, equine lysozyme, and S100b. OB mice treated with noopept had doubled antibody levels to ABeta peptide, but had no difference in antibodies for equine lysozyme or S100b. The effect of noopept on SO+NP mice was even greater. Antibody levels for ABeta peptide increased five times the normal level, but no effect was observed in equine lysozyme or S100b antibody levels (Ostrovskaya et. al, 2006). Discussion Effects of Noopept on Alzheimer’s Symptoms 6 As determined previously and confirmed by this study, olfactory bulbectomy in NMRI mice results in Alzheimer-like symptoms and behavior. OB mice display impaired cognitive function, including decreased spatial memory and suppressed immunity to amyloid proteins. Noopept, administered daily to olfactory bulbectomized mice, restores spatial memory and increases ABeta peptide antibody levels (Ostrovskaya et. al, 2006). Preference for quadrant 3 (the quadrant containing the hidden platform during training) and a significant number of entries into this quadrant indicates restored spatial memory. These improvements are comparable to normal spatial memory and antibody levels in SO mice treated with saline. Treatment with noopept does no affect antibody levels to equine lysozyme or S100b protein. This study proposes that a lack of immunity toward S100b may be the result of previously existing immune suppression in NMRI mice (Ostrovskaya et. al, 2006). Two additional studies by Ostrovskaya et. al evaluate additional properties of the nootropic noopept. The first focuses on the effects of noopept on expression of neurotrophins NGF (nerve growth factor) and BDNF (brain-derived growth factor) in rat hippocampus. Neurotrophins play a crucial role in cognitive function, most importantly in both short-term and long-term memory integration. Deficiency of neurotrophins has been linked to cognitive impairment in Alzheimer’s disease and many other neurodegenerative diseases. This study discovered that long-term administration of noopept does not result in increased tolerance, but continues intensifying NGF and BDNF synthesis. Therefore, by increasing expression of neurotrophins NGF and BDNF noopept is directly associated with the restoration of damaged neurons. This study concludes that in addition to the restorative properties of noopept, new evidence shows that it may also be an efficient preventative therapy when administered at the onset of Alzheimer’s disease (Ostrovskaya et. al, 2008). Effects of Noopept on Alzheimer’s Symptoms 7 A second study evaluates the immunological and neuroprotective effects of noopept in rats. Rats in this study were injected with amyloid beta (ABeta peptide) to simulate long-term memory impairment characteristic of Alzheimer’s disease. Mild cognitive impairment was normalized by treatment with noopept. A significant increase in antibodies to ABeta peptide was also observed. The most distinct discovery of this study is the cholinopositive effect exhibited by noopept. Previous research has determined that choline plays an important role in memory. Choline is an essential nutrient and the precursor molecule of acetylcholine, a neurotransmitter found in cell membranes. Acetyl choline is required for proper muscle function and memory consolidation (Ostrovskaya et. al, 2008). Piracetam and aniracetam, two analogues of noopept, are currently used to treat Alzheimer’s symptoms, but have no effect on many patients. Studies have found noopept to be five-hundred times more effective than piracetam and aniracetam and researchers hope to begin using it as a treatment for Alzheimer’s disease in the near future (Ostrovskaya et. al, 2006). Considering recent studies and research, it can be concluded that administration of noopept improves cognitive deficits resulting from neurodegenerative diseases. Studies involving additional animal models may be necessary to evaluate the efficacy of noopept in a variety of subjects. With additional studies, nootropic substances may finally provide a firm understanding of Alzheimer’s disease, as well as a method of prevention or treatment (Ostrovskaya et. al, 2006). Effects of Noopept on Alzheimer’s Symptoms 8 Bibliography (1) Ostrovskaya et. al "The Nootropic and Neuroprotective Proline-containing Dipeptide Noopept Restores Spatial Memory and Increases Immunoreactivity to Amyloid in an Alzheimer's Disease Model." Journal of Psychopharmacology 21.6 (2006): 611-19. (2) Casaite, Vida et. al. "Expression and Purification of Active Recombinant Equine Lysozyme in Escherichia Coli." Oxford Journals 22.11 (2009): 649-54.Http://www.oxfordjournals.org/. Oxford University Press, 8 July 2009. Web. 14 Mar. 2012. <http://peds.oxfordjournals.org/content/22/11/649.abstract>. (3) Hauschild, A. et. al. "Melanoma Research." Melanoma Research 9.2 (1999). Prognostic Significance of Serum S100B Detection Compared With routine blood parameters in advanced metastatic melanoma patients. Lippincott Williams & Wilkins, Inc., 1999. Web. 14 Mar. 2012. <http://journals.lww.com/melanomaresearch/Abstract/1999/04000/Prognostic_significance_o f_serum_S100B_detection.8.aspx>. (4) Ostrovskaya, et. al. "Noopept Stimulates the Expression of NGF and BDNF in Rat Hippocampus." Bulletin of Experimental Biology and Medicine 146.3 (2008): 334-37. <http://www.ncbi.nlm.nih.gov/pubmed/19240853>. (5) Ostrovskaya, et. al. “Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats).” Bulletin of Experimental Biology and Medicine 146.1 (2008): 77-80. <http://www.ncbi.nlm.nih.gov/pubmed/19145356>.