RATIONAL OF ANIMALS USE IN DRUG DISCOVERY

ABOUT AUTHORS:
Aruni Kumari, Ajit Kumar Thakur, Vikas Kumar*
Neuropharmacology Research Laboratory, Department of Pharmaceutics,
Indian Institute of Technology (Banaras Hindu University),
Varanasi-221 005, India
*vikas.phe@iitbhu.ac.in

ABSTRACT
Animals play a pivotal role in science and scientific technology. All the animals used in experiments are treated ethically following legislative rules. Small animal such as mice, turtles, frogs, rats etc. are used which has short span of reproductive cycle. Their population can be multiplied within six months. The use of animals in research is analyzed from the viewpoint of three distinct ethical approaches: contractarianism, utilitarianism and animal rights view. On contractarian point of view, research on animal is ethical to the extent that human as a social party should care about its well being. According to utilitarian point of view, harm caused to the sentient animal during research should be compensated with benefit to human society. From the animal rights view, use of animals in science is not in animal’s best interest. In this review, comprehensive information is provided on contribution of animal research in drug discovery and development.

REFERENCE ID: PHARMATUTOR-ART-1814

1. INTRODUCTION
Animal experimentation is the backbone of the medical and scientific research. But the main focus should be on input and output (Rowan, 1997). The use of animals in scientific investigation has been traced back to ancient history. For instance, the writings of Aristotle (384-322 B.C.) and Erasitratus (304-258 B.C.) indicate that they had studied the anatomy of various animals. Use of animals in scientific investigation is very important and ineluctable in the interest of human welfare(Baumans, 2004). Various alternatives have been designed like in-vitro methods, but these only acts as an adjunct and reduce the number of animals used. Also the rate of biotransformation is rapid in small laboratory animals than in human, which lead to species difference in response to drugs(Kumar et al., 2000).Certain life processes can only be investigated by using whole animal system asin-vitro alternatives provide limited information. At the same time, scientists are required to follow the legislative rules for ethical treatment of animals (Sahni,2000). In this review, through a systematic search, contributions made by animal research in drug discovery are compiled.

2. MATERIAL AND METHODS
We have highlighted the rational use of animals in drug discovery via scientific search engines such as PubMed, ScienceDirect, Google Scholar, Scopus etc. using key words animal, drug discovery, animal pharmacology and animal physiology.

3. MAJOR ADVANCES IN BASIC RESEARCH THAT DEPENDED ON ANIMALS
The animals were frequently used as a model organism in the early 19^th century for drug discovery. Vaccines for various diseases like smallpox, anthrax, rabies, typhoid were discovered using animal experimentation. In early 90s, treatment for rickets, Vitamin C, local anaesthetic, vaccine for tetanus, polio, diptheria, antibiotic(penicillin, streptomycin) was discovered which served the purpose of human well being. With the advent of 20^th century various modern developments were made which revolutionized the scientific era. Mechanism and treatment of disease like cancer, AIDS, influenza, and several other fatal diseases were discovered. This contribution of animal life in experiments saved millions of human life across the world (Table 1).

4. CONTRIBUTION OF ANIMALS USE IN DRUG DISCOVERY
4.1. CNS Disorders:Animal experimentation has made a significant contribution in this field in understanding various disorders and invention of its cure.Monkeys are used to understand and cure Parkinson’s disease (Redmond, 2012). Now several drugs are available for its treatment.With the findings in mouse model of neuro-developmental disorders such as fragile X,Rett syndrome, Down syndrome, and neurofibromatosis type I suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations.Earlier brain development during neuronal disorder and any abnormalities were considered irreversible in adulthood (Castren,2012).P7C3,an aminopropyl carbazole has proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. This has been found that this chemical is efficacious inprotecting dopaminergic neurons of the substantianigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,in a mouse model of Parkinson’s disease. An active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS).It has been proposed that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS (Teslaetal., 2012). A multifunctional DNA/RNA-binding protein TDP-43 has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine and tamoxifen) have been tested in a FTLD-U mouse model with TDP-43 proteinopathies.Some behavioral improvements has been reported upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice,as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies(Wang etal., 2012). Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons.By screening a zebrafish model of ALS Epha4, a receptor in the Ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans has been identified. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention (Van Hoeckeet al., 2012). Middle cerebral artery occlusion(MCAO) is a widely used experimental technique in rodents to model both the short-term pathological events and longer term neuroanatomical and functional damage associated with focal ischemia. Various neurobehavioral tasks have been developed to assess the motor and cognitive dysfunctions associated with MCAO in rodents, and these studies have revealed deficits related to long-term sensorimotor function, as well as retention of spatial memory. Combined behavioral results from post-MCAO mice provide evidence of a RAP deficit as well as deficits in spatial, non-spatial, and motor learning. Overall results support a fuller characterization of behavioral deficits in auditory processing after MCAO (Troungetal., 2012). Repulsive guidance molecule a (RGMa) is a neurite growth inhibitor. It is of great interest in the study of CNS neuronal regeneration. RNA interference (RNAi) as a means of suppressing the expression of RGMa has been adopted and observed the improvement in axonal regeneration and neurological function of rats after cerebral ischemic injury. RGMa in rat brains after middle cerebral artery occlusion (MCAO) can be down-regulated by RNAi successfully, which may lead to improved axonal growth and neural anatomy plasticity, as well as neuron functional recovery(Fengetal., 2012). High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. The involvement of HMGB1 in traumatic brain injury (TBI) has been examined and the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury is evaluated by using rat or mice model(Okuma etal., 2012). Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. This disease is caused by expansion of a CAG trinucleotide repeat and manifests with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. MB(methylene blue) increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in a Drosophila melanogaster model of HD, and reduced disease phenotypes in R6/2 HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and protein in-vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD(Sotang et al., 2012). Comparative neuroprotective potential of silymarin, piracetam and protocatechuic acid ethyl ester (PCA) was evaluated in focal ischemic rats. Various pharmacological, biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite content, brain water content) and behavioural (memory impairment, motor control, neurological score) including infarct size and histopathological alterations were evaluated.Silymarin was found to be more effective than other(Muley etal., 2012). Incorporation of adeno-associated virus and short-hairpin RNA against superoxide dismutase-1 bypassed the blood-brain barrier to target the spinal cord and dorsal root ganglia. The therapeutic vector effectively suppressed mRNA and protein expression of endogenous superoxide dismutase-1 in the lumbar spinal cord and dorsal root ganglia. Moreover, neither neurological side effects nor toxicity due to the incorporated short-hairpin RNA occurred after the injection. Thus it was proposed that this approach could be developed into novel therapies for motor neuron diseases and chronic pain conditions, such as complex regional pain syndrome, through silencing of the genes responsible for pathologies in the spinal cord and dorsal root ganglia(Hirai etal., 2012). The pharmacological activity of the essential oil obtained from Spirantheraodoratissima leaves and its major component on the murine CNS has been evaluated. It showed possible anxiolytic-like effect and the underlying mechanisms involved were also investigated. β-caryophyllene, the main component of this essential oil, and has anti inflammatory activity. Spirantheraodoratissimais used in folk medicine to treat renal and hepatic diseases, stomachache, headaches and rheumatism(Galdino etal., 2012).

4.2. GIT Disorders: Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure(DiCarlo etal., 2012). Approximately 25% of the patients have established colorectal liver metastasis. Optimal management of disseminated disease requires therapies targeting multiple stages in hepatic colorectal cancer metastasis development. To facilitate this, biologically accurate in-vivo models are required. Early colonic cancer liver metastases development was studied using BDIX and Sprague-Dawley rat strains with human HT29 and rat DHDK12 colonic cancer cell lines(Robertson etal., 2008). The protective effect of electro-acupuncture (EA) pretreatment on acetylsalicylic acid (ASA)-induced ulceration in rats was investigated. Protection was thought to be through gastric defense component(Hwang et al., 2009). The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses.Thus GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined(Hellstrom,2009). The expression of substance P (SP) in the airway mucosa of guinea pigs was observed with repetitive esophageal stimulation by hydrochloric acid (HCL). Airway neurogenic inflammation was found in guinea pigs with repetitive esophageal stimulation by HCL, which maybe closely related to the pathogenesis of gastro-esophageal reflux disease (Liet al.,2009). Fluoro-D-glucose position emission tomography (FDG-PET) would allow for the introduction of metabolic imaging into intraoperative and minimally invasive settings. Through in-vitro and in-vivoexperimentation an evaluation of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescently labeled glucose molecule has been presented as a molecular beacon of glucose utilization. The competitive inhibition of 2-NBDG uptake by excess free glucose is directly compared against FDG uptake inhibition in cultured cells. 2-NBDG uptake in the brain of a mouse experiencing a generalized seizure was measured, as well as in subcutaneously implanted tumors in mice during fed and fasting states. Localization of 2-NBDG into malignant tissues was studied by laser scanning microscopy. The clinical relevance of 2-NBDG imaging is examined by performing fluorescence colonoscopy, and by correlating preoperative FDG-PET with intraoperative fluorescence imaging. 2-NBDG exhibits a similar uptake inhibition to FDG by excess glucose in the growth media. Uptake was significantly increased in the brain of an animal experiencing seizure versus control, and in subcutaneous tumors after the animals are kept nil per os (NPO) for 24 h versus ad libitum feeding. The clinical utility of 2-NBDG is confirmed by the demonstration of very high target-to-background ratios in minimally invasive and intraoperative imaging of malignant lesions. We present an optical analog of FDG-PET to extend the applicability of metabolic imaging to minimally invasive and intraoperative settings (Sheth et al., 2009). The preventive effect of sodium butyrate in the appearance of aberrant crypt foci (ACF) in rats was evaluated after induction with the carcinogen 1,2-dimethylhydrazine (DMH). The use of sodium butyrate together with the induction of colorectal cancer was not effective in the prevention of the disease progression (Silva et al., 2010). The experimental infection of newborn calves with bovine norovirus was used as a homologous large animal model to study the pathogenesis of norovirus infection and to determine target cells for viral replication(Otto et al., 2011). Experiment done on Sprague Dawley male rats showed that a significant alteration in the enzyme activity as well as changes in the structure and function of the intestine in the presence of the pro-carcinogen, DMH(1,2 Dimethylhydrazine), which suggests the possible chemopreventive efficacy of NSAIDs against the intestinal cancer(Mittalet al., 2008).

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4.3. Respiratory Disorders: The respiratory system acts as a portal into the human body for airborne materials, which may gain access via the administration of medicines or inadvertently during inhalation of ambient air (e.g. air pollution). Due to increased rate of death from respiratory disease than from coronary heart disease or non-respiratory cancer experiment on animal is gaining momentum for understanding the mechanisms of human lung biology, especially in injury and repair events. It is now a principal focus within the field of respiratory medicine (Berube,2011).The methyl-CpG binding protein 2 (Mecp2)genesencodes a nuclear transcriptional modulator highly expressed in post-mitotic neurons. Mutations of this gene cause a large spectrum of neurological disorders in humans. A set of sensorimotor tests and respiratory metabolism measurements was done in a longitudinal study of the Mecp2-null male mice. Motor functions and respiratory metabolism was found to be severally impaired. A detailed description of these gradual defects may help to identify their neuronal origin and to elaborate novel therapeutic strategies (Pratte et al., 2011).Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 show a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. The absence of Mecp2 during brain development does not irreversibly compromise brain function.So MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete (Robinson et al.,2012).For better understanding and progression of lung cancer an experiment was done on mice with knockout (KO) of G-protein coupled receptor 5A(Gprc 5a). It was found that lung tumor genesis in the Gprc5a-KO mouse model is augmented by NNK and gene expression changes induced by tobacco carcinogen(s) may be conserved between mouse and human lung epithelial cells (Fujimoto et al., 2010).New surface-active agents in waterproofing sprays were tested for acute inhalation toxicity using isolated perfused lung of rat. This pre-test prevented many deathsdue lung infection (Fischer et al., 2012)

4.4. Acquired Immunodeficiency Syndrome (AIDS): Patients with AIDS often develop cognitive and motor dysfunction that results from damage to synapses and death of neurons in brain regions such as the hippocampus and basal ganglia. This brain syndrome is called AIDS dementia or HIV encephalitis. Two neurotoxic HIV-1 proteins have been identified, the viral coat protein gp120 and the transcription regulator Tat. Each of these proteins can induce apoptosis of cultured neurons and can render neurons vulnerable to excitotoxicity and oxidative stress. Gp120 and Tat also cause neuronal dysfunction and death in rodentsin-vivo. Both gp120 and Tat disrupt neuronal calcium homeostasis. A better understanding of how gp120 and Tat disrupt neuronal calcium homeostasis may lead to the development of novel treatments for AIDS patients(Haughey and Mattson, 2002). At least in some neuronal cell types, gp120-induced neurotoxicity can be prevented by antagonists of L-type voltage-dependent calcium channels or by antagonists of N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor). Degradation of endogenous glutamate also protects neurons from gp120-related neuronal injury, suggesting that gp120 and glutamate are both necessary for neuronal cell death as synergistic effectors(Lipton,1991). Clinically tolerated calcium channel antagonists and NMDA antagonists have potential for trials in humans with AIDS dementia in the near future(Lipton, 1994). Recent experimental evidence suggests that disturbance by HIV-1 results not only in neuronal injury and death but also in impairment of neurogenesis.Various methods are used to assess HIV burden in CNS (Kaul, 2008;Wiley et al., 1994). Various in-vivo and cell culture studies indicate that cells of neuroectodermal origin, particularly astrocytes, may also be infected by HIV-1. These cells restrict virus production and serve as reservoirs for HIV-1. Entry of HIV-1 into neuroectodermalcells is independent of the CD4 receptor, and a number of different cell-surface molecules have been implicated as alternate receptors of HIV-1. Future challenges will be to develop strategies to prevent HIV-1 spread in the brain, bolster intrinsic defense mechanisms of the brain and to elucidate the impact of long-term persistence of HIV-1 on CNS functions in individuals without AIDS(Kramer-Hammerleet al., 2005). In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV-associated dementia and the presence and relative quantity of immunocytochemical markers for HIV-1 (gp41 antibody), and for macrophages and microglia (HAM-56 antibody). Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity(Glasset al., 1995).

4.5. Cancer:Chemopreventive potential of curcumin against skin cancer was experimentally found using mice(Philips, 2013).Bone marrow stromal cells, precoated on the implant, accelerate the formation of new sinusoidal blood vessels with vascular integrity at the micro capillary level that enhances the recruitment hematopoietic progenitor cells to the site. This implantable construct can serve as a tool enabling the study of hematopoiesis(Lee et al.,2012). An animal model system was used for evaluating targeted ultrasound (US) contrast agents binding using adenoviral (Ad) vectors to modulate cellular receptor expression. An Ad vector encoding an extracellular hemagglutinin (HA) epitope tag and a green fluorescent protein (GFP) reporter was used to regulate receptor expression. A low and high receptor density (in breast cancer tumor bearing mice) was achieved by varying the Ad dose with a low plaque forming unit (PFU) on day 1 and high PFU on day 2 of experimentation(Saini et al., 2013).Liver tumour was induced in male C3H mice using diethylnitrosamine(DEN). Micewere routinely scanned by noninvasive magnetic resonance imaging (MRI) using a T2-weighted 3D sequence on regular intervals. Liver tumors became detectable in both experiments when they exceeded a diameter of less than 1 mm. This led to early detection of tumour onset hence it can be cured easily (Schimd et al., 2012).

4.6. Diabetes: Interleukin-6 and several of its family members but not other well-recognized insulin sensitizing agents were identified as potent hypoglycemic factors.This experimental system servesas a powerful and flexible in-vivo screening platform for identifying genes that modulate complex behavioral and metabolic phenotypes(Chen et al., 2012). An inbred rat model of diabetic embryopathy, was developed in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Genes controlling the embryonic maldevelopment in a diabetic environment was found. The fetal outcome in inbred Sprague-Dawley rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats, no skeletal malformations in diabetic pregnancy) was compared.Final conclusion was that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations(Nordquist et al., 2012). The relation of production ghrelin with hyperphagiain diabetic state was found using spontaneous Torii Rat(Mifuneet al., 2012). Diabetes mellitus is a metabolic disorder associated with structural and functional alterations of various organ systems including the central nervous system. AGM(Agmatine)posttreatment reduced cerebral infarct size and neurological deficit expression in diabetic rats subjected to MCAO. The reduced infarct size was associated with a decrease in apoptosis and NOS(Nitric oxide synthase) expression(Cui et al., 2012).Mouse model of heart failure are commonly used today to understand the cardiac biology and convert the specific advancement into new drug(Brekenridge, 2010).

4.7. Thyroid Disorders: Effects of methimazole (a major anti-thyroid drug) administration to rat dams on the development of cerebellum of their pups has been investigated with morphological, morphometrical and functional procedures (Hasebeet al., 2008)

5. CONCLUSION
The use of animals is the heart of scientific and medical research.Their contribution especially in the field of medicine is immeasurable. Legislative rules have been prepared to give ethical treatment to them. To the best regard of animals, their experimentation has been abolished from the undergraduate syllabus. Care is taken to provide better ambience and least possible pain during testing. Sacrifice of their life is generally compromised forthe benefit of human society. Nowadays in-vitro methods are mostly used for research purpose but life process can only be revealed using whole animal system.

Table 1: Advances in basic research that depended on animals

Source: Research Defence Society & Coalition for Medical Progress, 2007.

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REFERENCES

• Baumans, V., 2004. Use of animals in experimental research: an ethical dilemma? Gene Therapy. 11(Suppl 1), S64-S66.
• Berube, K.A., 2011. Alternatives for lung research, stuck between a rat and a hard place. Alternatives to Laboratory Animals.39(2), 121-130.
• Breckenridge, R., 2010. Heart failure and mouse models. Disease Model and Mechanism. 3(3-4), 138-143.
• Castren, E., Elgersma, Y., Maffei, L., Hagerman, R., 2012. Treatment of neurodevelopmental disorder in adulthood.Journal of Neuroscience.32(41), 14074-14079.
• Chen, C.A., Carolan, P.C., Annes, J.P., 2012. In-vivo screening for secreted proteins that modulate glucose handling identifies interleukin-6 family members as potent hypoglycemic agents. PLoS One. 7(9), e44600.
• Cui, H., Lee, J.H., Kim, J.Y., Koo, B.N., Lee, J.E., 2012. The neuroprotective effect of agmatine after focal cerebral ischemia in diabetic rats.Journal of Neurosurgical Anaesthesiology.24(1), 39-50.
• DiCarlo, A.L., Jackson, I.L., Shah, J.R., Czarniecki, C.W., Maidment, B.W., Williams, J.P., 2012. Development and licensure of medical countermeasures to treat lung damage resulting from a radiological or nuclear incident. Radiation Research.177(5), 717-721.
• Feng, J., Wang, T., Li, Q., Wu, X., Qin, X., 2012. RNA interference against repulsive guidance molecule A improves axon sprout and neural function recovery of rats after MCAO/reperfusion. Experimental Neurology. 238(2), 235-242.
• Fischer, M., Koch, W., Windt, H., Dasenbrock, C., 2012. A pilot study on the refinement of acute inhalation toxicity studies, the isolated perfused rat lung as a screening tool for surface-active substances. Alternative to Laboratory Animals.40(4), 199-209.
• Fujimoto, J., Kadara, H., Men, T., van Pelt, C., Lotan, D., Lotan, R., 2010. Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice. PLoS One. 5(7), e11847.
• Galdino, P.M., Nascimento, M.V., Florentino, I.F., Lino, R.C., Fajemiroye, J.O., Chaibub, B.A., de Paula, J.R., de Lima, T.C., Costa, E.A., 2012. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice.Progress in Neuro-psychopharmacology & Biological Psychiatry.38(2), 276-284.
• Glass, J.D., Fedor, H., Wesselingh, S.L., McArthur, J.C., 1995. Immunocytochemical quantization of human immunodeficiency virus in the brain, correlations with dementia.Annals of Neurology.38, 755-762.
• Hasebe, M., Matsumoto, I., Imagawa, T., Uehara, M., 2008.Effects of an anti-thyroid drug, methimazole, administration to rat dams on the cerebellar cortex development in their pups.International Journal of Developmental Neuroscience.26(5), 409-414.
• Haughey, N. J., Mattson, M. P., 2002. Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120.Journal of Acquired Immunodeficiency Syndrome. 31 Suppl 2, S55-61.
• Hellström, P. M., 2009. GLP-1, broadening the incretin concept to involve gut motility. Regulatory Peptides. 156(1-3), 9-12.
• Hirai, T., Enomoto, M., Machida, A., Yamamoto, M., Kuwahara, H., Tajiri, M., Hirai, Y., Sotome, S., Mizusawa, H., Shinomiya, K., Okawa, A., Yokota, T., 2012.Intrathecal shRNA-AAV9 inhibits target protein expression in the spinal cord and dorsal root ganglia of adult mice. Human Gene Therapy Model.23(2), 119-127.
• Hwang, H.S., Han, K.J., Ryu, Y.H., Yang, E.J., Kim, Y.S., Jeong, S.Y., Lee, Y.S., Lee, M.S., Koo, S. T., Choi, S. M., 2009. Protective effects of electroacupuncture on acetylsalicylic acid-induced acute gastritis in rats.Journal of Gasteroenterology.15(8), 973-977.
• Kaul, M., 2008.HIV’s double strike at the brain, neuronal toxicity and compromised neurogenesis.Frontierin Bioscience.13, 2484-2494.
• Kramer-Hämmerle, S., Rothenaigner, I., Wolff, H., Bell, J.E., Brack-Werner, R., 2005. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus.Virus Research. 111(2), 194-213.
• Kumar, V., Singh, P.N., Mishra, B., 2000. Animal experimentation: A rational approach towards drug development. Indian Journal of Experimental Biology.38, 540-548.
• Lee, J., Li, M., Milwid, J., Dunham, J., Vinegoni, C., Gorbatov, R., Iwamoto, Y., Wang, F., Shen, K., Hatfield, K., Enger, M., Shafiee, S., McCormack, E., Ebert, B.L., Weissleder, R., Yarmush, M.R., Parekkadan, B., 2012. Implantable microenvironments to attract hematopoietic stem/cancer cells.Proceedings of the National Academy of Sciences of The United States of America.109(48), 19638-19643.
• Li, Q.Z., Kong, L.F., Zhang, S.N., Zhong, Z.S., Zhang, B.H., Liu, X.F., 2009. The expression of substance P in airway mucosa of guinea pigs with repetitive esophageal stimulation by hydrochloric acid.Chinese Journal of Tuberculosis and Respiratory Diseases.32(6), 426-429.
• Lipton, S.A., 1991. HIV-related neurotoxicity. Brain Pathology. 1(3), 193-199.
• Lipton, S.A., 1994. Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists. Developmental Neuroscience. 16(3-4), 145-151.
• Mifune, H., Nishi, Y., Tajiri, Y., Masuyama, T., Hosoda, H., Kangawa, K., Kojima, M., 2012. Increased production of active ghrelin is relevant to hyperphagia in nonobese spontaneously diabetic Torii rats. Metabolism, Clinical and Experimental.61(4), 491-495.
• Mittal, N., Kanwar, S.S., Sanyal, S.N., 2008. Effect of non-steroidal anti-inflammatory drugs and the pro-carcinogen 1,2 dimethylhydrazine on the rat intestinal membrane structure and function.NutricionHospitalaria. 23(5), 439-448.
• Muley, M.M., Thakare,V.N., Patil, R.R., Kshirsagar, A.D., Naik, S.R., 2012. Silymarin improves the behavioural, biochemical and histoarchitecture alterations in focal ischemic rats, a comparative evaluation with piracetam and protocatachuic acid. Pharmacology Biochemistry and Behavior. 102(2), 286-293.
• Nordquist, N., Luthman, H., Pettersson, U., Eriksson,U.J., 2012. Linkage study of embryopathy-polygenic inheritance of diabetes-induced skeletal malformations in the rat. Reproductive Toxicology. 33(3), 297-307.
• Okuma, Y., Liu, K., Wake, H., Zhang, J., Maruo, T., Date, I., Yoshino, T., Ohtsuka, A., Otani, N., Tomura, S., Shima, K., Yamamoto, Y., Yamamoto, H., Takahashi, H.K., Mori, S., Nishibori, M., 2012. Anti-high mobility group box-1 antibody therapy for traumatic brain injury.Annals of Neurology.72(3), 373-384.
• Otto, P.H., Clarke, I.N., Lambden, P.R., Salim, O., Reetz, J., Liebler-Tenorio, E.M., 2011. Infection of calves with bovine norovirus GIII.1 strain Jena virus, an experimental model to study the pathogenesis of norovirus infection. Journal of Virology.85(22), 12013-12021.
• Phillips, J., Moore-Medlin, T., Sonavane, K., Ekshyyan, O., McLarty, J., Nathan, C.A., 2013.Curcumin Inhibits UV Radiation-Induced Skin Cancer in SKH-1 Mice.OtolaryngolHead and Neck Surgery. 148(5), 797-803.
• Pratte, M., Panayotis, N.,Ghata, A., Villard, L., Roux, J.C., 2011.Progressive motor and respiratory metabolism deficits in post-weaning Mecp2-null male mice.Behavioral Brain Research.216(1), 313-320.
• Redmond, Jr., D.E., 2012. Using Monkeys to Understand and Cure Parkinson Disease. HastingsCenter Report.42, S7-S11.
• Research Defence Society & Coalition for Medical Progress, 2007. Medical advances and animal research.Published byRDS: Understanding Animal Research in Medicine and Coalition for Medical Progress.
• Robertson, J.H., Yang, S.Y., Iga, A.M., Seifalian, A.M., Winslet, M.C., 2008. An in-vivo rat model for early development of colorectal cancer metastasis to liver.International Journal of Experimental Pathology.89(6), 447-457.
• Robinson, L., Guy, J., McKay, L., Brockett, E., Spike, R.C., Selfridge, J., De Sousa, D., Merusi, C., Riedel, G., Bird, A., Cobb, S.R., 2012. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain. 135(Pt 9), 2699-2710.
• Rowan, A.N., 1997.The benefits and ethics of animal research. Scientific American. 276(2), 79-93.
• Sahni, S.K., 2000. Guideline for care and use of animals in Scientific Research. Indian National Science Academy, First Edition (Revised). New Delhi.
• Saini, R., Sorace, A.G., Warram, J.M., Mahoney, M.J., Zinn, K.R., Hoyt, K., 2013. An animal model allowing controlled receptor expression for molecular ultrasound imaging. Ultrasound in Medicine and Biology.39(1), 172-180.
• Schmid, A., Rignall, B., Pichler, B.J., Schwarz, M., 2012. Quantitative analysis of the growth kinetics of chemically induced mouse liver tumors by magnetic resonance imaging. Toxicological Sciences. 126(1), 52-59.
• Sheth, R.A., Josephson, L., Mahmood, U., 2009. Evaluation and clinically relevant applications of a fluorescent imaging analog to fluorodeoxyglucose positron emission tomography.Journal of Biomedical Optics.14(6), 064014.
• Silva, F.G., Penido, L.C., Valente, F.X., Mendes, M.C., Rosa, D.D., Gloria, M.B., PeluzioMdo, C., 2010. Sodium butyrate does not decrease the evolution of precancerous lesions in rats.ActaCirurgicaCrasileira. 25(6), 507-512.
• Sontag, E.M., Lotz, G.P., Agrawal, N., Tran, A., Aron, R., Yang, G., Necula, M., Lau, A., Finkbeiner, S., Glabe, C., Marsh, J.L., Muchowski, P.J., Thompson, L.M., 2012.Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models. Journal of Neurosciences.32(32), 11109-11119.
• Tesla, R., Wolf, H.P., Xu, P., Drawbridge, J., Estill, S. J., Huntington, P., McDaniel, L., Knobbe, W., Burket, A., Tran, S., Starwalt, R., Morlock, L., Naidoo, J., Williams, N. S., Ready, J.M., McKnight, S. L., Pieper, A. A., 2012. Neuroprotective efficacy of aminopropylcarbazoles in a mouse model of amyotrophic lateral sclerosis.Proccedings of the National Academy of Sciences of the United States of America.109(42), 17016-17021.
• Truong, D.T., Venna, V.R., McCullough, L.D., Fitch, R.H., 2012.Deficits in auditory, cognitive, and motor processing following reversible middle cerebral artery occlusion in mice. Experimental Neurology. 238(2), 114-121.
• Van Hoecke, A., Schoonaert, L., Lemmens, R., Timmers, M., Staats, K.A., Laird, A.S., Peeters, E., Philips, T., Goris, A., Dubois, B., Andersen, P.M., Al-Chalabi, A., Thijs, V., Turnley, A.M., van Vught, P.W., Veldink, J.H., Hardiman, O., Van Den Bosch, L., Gonzalez-Perez, P., Van Damme, P., Brown, R.H., Jr, van den Berg, L.H., Robberecht, W., 2012. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nature Medicine. 18 (9), 1418-1422.
• Wang, I.F., Guo, B.S., Liu, Y.C., Wu, C.C., Yang, C.H., Tsai, K.J., Shen, C.K., 2012. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proceedings of the National Academy of Sciences of the United States of America.109 (37), 15024-15029.
• Wiley, C.A., Masliah, E., Achim, C.L., 1994.Measurement of CNS HIV burden and its association with neurologic damage. Advanced Neuroimmunology. 4, 319-325.

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