Microglia and regulation of inflammationmediated neurodegeneration: Prevention and treatment by phytochemicals and metabolic nutrients

Authors

  • Rajagopal Shanmuga Sundaram
  • Lakshminarayanan Gowtham

DOI:

https://doi.org/10.22377/ijgp.v6i2.243

Abstract

Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a
critical mechanism responsible for the progressive nature of neurodegeneration. Microglias are the resident innate immune cells in the central nervous system and produce a barrage of factors (ILs, TNF α, NO, PGs, SOD) that are toxic to neurons. Evidence supports that the unregulated activation of microglia, in response to environmental toxins, endogenous proteins and neuronal death, results in the production of toxic factors that propagate neuronal injury. Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti‑inflammatory and / or antioxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia‑derived chronic inflammatory responses play a pathological role in the central nervous system, anti‑inflammatory herbal medicine and its constituents are being proved to be potent neuroprotectors against various brain pathologies. Structural diversity of medicinal herbs makes them a valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics and high‑throughput screening. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons and explain how the
microglial response to neuronal damage results in a self‑propelling cycle of neuron death. This article synthesizes what we know about these destructive processes, while offering an insight into a new avenue of treatment involving phytochemicals and other nutrients.
Key words: Astrocyte, flavonoids, free radical scavengers, microglia, neuroinflammation, phytochemicals

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References

Blaylock RL. Neurodegeneration and aging of the central nervous

system: prevention and treatment by phytochemicals and

metabolic nutrients. Integr Med 1998;1:117‑33.

Singh RP, Sharad S, Kapur S. Free radicals and oxidative stress in

neurodegenerative diseases: Relevance of dietary antioxidants.

J Indian Acad Clin Med 2004;5:218‑25.

Standaert DG, Young AB. Treatment of central nervous

degenerative disorders. In: Brunton LL, Lazo P, Parker KL,

editors. Goodman and Gilman’s The Pharmacological Basis of

Therapeutics. 11th ed. New Delhi: McGraw‑Hill; 2006. p. 527‑46.

Block ML, Hong JS. Microglia and inflammation‑mediated

neurodegeneration: multiple triggers with a common mechanism.

Progr Neurobiol 2005:76;77‑98.

Beal MF. Aging, energy and oxidative stress in neurodegenerative

diseases. Ann Neurol 1995;38:357‑66.

Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B. Microglial

activation‑mediated delayed and progressive degeneration of rat

nigral dopaminergic neurons: relevance to Parkinson’s disease.

J Neurochem 2002;81:1285‑97.

Block ML, Wu X, Pei Z, Li G, Wang T, Qin L, et al. Nanometer

size diesel exhaust particles are selectively toxic to dopaminergic

neurons: the role of microglia, phagocytosis, and NADPH oxidase.

FASEB J 2004;18:1618‑20.

Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong JS. Microglias

enhance beta‑amyloid peptide‑induced toxicity in cortical and

mesencephalic neurons by producing reactive oxygen species.

J Neurochem 2002;83:973‑83.

Betarbet R, Sherer TB, MacKenzie G, Garcia‑Osuna M, Panov AV,

Greenamyre JT. Chronic systemic pesticide exposure reproduces

features of Parkinson’s disease. Nat Neueurosci 2000;3:1301‑6.

Greenamyre JT, MacKenzie G, Peng TI, Stephans SE. Mitochondrial

dysfunction in Parkinson’s disease. Biochem Soc Symp 1999;66:85‑97.

Campbell A, Oldham M, Becaria A, Bondy SC, Meacher D,

Sioutas C, et al. Particulate matter in polluted air may increase

biomarkers of inflammation in mouse brain. Neurotoxicology

;26:133‑40.

Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al.

Aggregated alpha‑synuclein activates microglia: a process

leading to disease progression in Parkinson’s disease. FASEB J

;19:533‑42.

Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. Prog

Neurobiol 1999;57:563‑81.

Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM,

Veerhuis R, et al. Neuroinflammation in Alzheimer’s disease and

prion disease. Glia 2002;40:232‑9.

Sánchez‑Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF,

Martin A. Decreased levels of plasma vitamin C and increased

concentrations of inflammatory and oxidative stress markers after

stroke. Stroke 2003;35:163‑8.

Wenk GL. Neuropathologic changes in Alzheimer’s disease. J Clin

Psychiatry 1995;64Suppl 9:7‑10.

Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: Intrinsic

immuneffector cell of the brain. Brain Res Brain Res Rev

;20:269‑87.

Gremo F, Sogos V, Ennas MG, Meloni A, Persichini T, Colasanti M,

et al. Features and functions of human microglia cells. Adv Exp

Med Biol 1997;429:79‑97.

Stoll G, Jander S. The role of microglia and macrophages in the

pathophysiology of the CNS. Prog Neurobiol 1999;58:233‑47.

Kreutzberg GW. Microglia: A sensor for pathological events in the

CNS. Trends Neurosci 1996;19:312‑18.

Minghetti L, Levi G. Microglia as effector cells in brain damage

and repair: Focus on prostanoids and nitric oxide. Prog Neurobiol

;54:99‑125.

Gonzalez‑Scarano F, Baltuch G. Microglia as mediators of

inflammatory and degenerative diseases. Annu Rev Neurosci

;22:219‑40.

Araque A, Perea G. Glial modulation of synaptic transmission in

culture. Glia 2004;47:241‑8.

Vesce S, Bezzi P, Volterra A. The active role of astrocytes in synaptic

transmission. Cell Mol Life Sci 1999;56:991‑1000.

Aschner M. Astrocytes as mediators of immune and inflammatory

responses in the CNS. Neurotoxicology 1998;19:269‑81.

Galea E, Feinstein DL, Reis DJ. Induction of calcium‑independent

nitric oxide synthase activity in primary rat glial cultures. Proc

Natl Acad Sci U S A 1992;89:10945‑9.

Sawada M, Kondo N, Suzumura A, Marunouchi T. Production of

tumor necrosis factor‑alpha by microglia and astrocytes in culture.

Brain Res 1989;491:394‑7.

Simmons ML, Murphy S. Induction of nitric oxide synthase in

glial cells. J Neurochem 1992;59:897‑905.

Becher B, Prat A, Antel JP. Brain‑immune connection:

Immunoregulatory properties of CNS resident cells. Glia

;29:293‑304.

Nakamura Y. Regulating factors for microglial activation. Biol

Pharm Bull 2002;25:945‑53.

Ho LJ, Lai JH. Chinese herbs as immunomodulators and potential

disease‑modifying antirheumatic drugs in autoimmune disorders.

Curr Drug Metab 2004;5:181‑92.

Li FQ, Lu XZ, Liang XB, Zhou HF, Xue B, Liu XY, et al. Triptolide,

a Chinese herbal extract, protects dopaminergic neurons from

inflammation‑mediated damage through inhibition of microglial

activation. J Neuroimmunol 2004;148:24‑31.

Ward PA, Warren JS, Johnson KJ. Oxygen radicals, inflammation,

and tissue injury. Free Radic Biol Med 1988;5:403‑8.

Henson PM, Johnston RB Jr. Tissue injury in inflammation. Oxidants,

proteinases, and cationic proteins. J Clin Invest 1987;79:669‑74.

Rankin JA. Biological mediators of acute inflammation. AACN

Clin Issues 2004;15:3‑17.

Halliwell B. Oxygen radicals, nitric oxide and human inflammatory

joint disease. Ann Rheum Dis 1995;54:505‑10.

Nakajima K, Kohsaka S. Microglia: Activation and their significance

in the central nervous system. J Biochem 2001;130:169‑75.

Liu B, Hong JS. Role of microglia in inflammation‑mediated

neurodegenerative diseases: Mechanisms and strategies for

therapeutic intervention. J Pharmacol Exp Ther 2003;304:1‑7.

Chavarria A, Alcocer‑Varela J. Is damage in central nervous system

due to inflammation? Autoimmun Rev 2004;3:251‑60.

Popovich PG, Jones TB. Manipulating neuroinflammatory

reactions in the injured spinal cord: Back to basics. Trends

Pharmacol Sci 2003;24:13‑7.

von Knethen A, Lotero A, Brune B. Etoposide and cisplatin induced

apoptosis in activated RAW 264.7 macrophages is attenuated by

cAMP‑induced gene expression. Oncogene 1998;17:387‑94.

Albina JE, Cui S, Mateo RB, Reichner JS. Nitric oxide‑mediated

apoptosis in murine peritoneal macrophages. J Immunol

;150:5080‑5.

Adler B, Adler H, Jungi TW, Peterhans E. Interferon‑alpha primes

macrophages for lipopolysaccharide‑induced apoptosis. Biochem

Biophys Res Commun 1995;215:921‑7.

Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS.

Molecular consequences of activated microglia in the brain:

Overactivation induces apoptosis. J Neurochem 2001;77:182‑9.

Lee P, Lee J, Kim S, Lee MS, Yagita H, Kim SY, et al. NO as an

autocrine mediator in the apoptosis of activated microglial cells:

Correlation between activation and apoptosis of microglial cells.

Brain Res 2001;892:380‑5.

Suk K, Lee J, Hur J, Kim YS, Lee M, Cha S, et al. Activation‑induced

cell death of rat astrocytes. Brain Res 2001;900:342‑7.

Donjerkovic D, Scott DW. Activation‑induced cell death in B

lymphocytes. Cell Res 2000;10:179‑92.

Crispe IN. Death and destruction of activated T lymphocytes.

Immunol Res 1999;19:143‑57.

Kingham PJ, Cuzner ML, Pocock JM. Apoptotic pathways mobilized

in microglia and neurons as a consequence of chromogranin

A‑induced microglial activation. J Neurochem 1999;73:538‑47.

Kingham PJ, Pocock JM. Microglial apoptosis induced by

chromogranin A is mediated by mitochondrial depolarisation

and the permeability transition but not by cytochrome c release.

J Neurochem 2000;74:1452‑62.

Yang MS, Park EJ, Sohn S, Kwon HJ, Shin WH, Pyo HK, et al.

Interleukin‑13 and ‑14 induce death of activated microglia. Glia

;38:273‑80.

Takano K, Nakamura Y, Yoneda Y. Microglialcell death induced

by a low concentration of polyamines. Neurosci 2003;120:961‑67.

Lee J, Hur J, Lee P, Kim JY, Cho N, Kim SY, et al. Dual role of

inflammatory stimuli in activation‑induced cell death of mouse

microglial cells: initiation of two separate apoptotic pathways via

induction of interferon regulatory factor‑1 and caspase‑11. J Biol

Chem 2001;276:32956‑65.

Lee H, Cha S, Lee MS, Cho GJ, Choi WS, Suk K. Role of

antiproliferative B cell translocation gene‑1 as an apoptotic

sensitizer in activation induced cell death of brain microglia.

J Immunol 2003;171:5802‑11.

Suk K, Kim SY, Kim H. Essential role of caspase‑11 in activationinduced

cell death of rat astrocytes. J Neurochem 2002;80:230‑8.

Drache B, Diehl GE, Beyreuther K, Perlmutter LS, Konig G.

bcl‑xl‑specific antibody labels activated microglia associated with

Alzheimer’s disease and other pathological states. J Neurosci Res

;47:98‑108.

Migheli A, Cavalla P, Piva R, Giordana MT, Schiffer D. bcl‑2

protein expression in aged brain and neurodegenerative diseases.

Neuroreport 1994;5:1906‑8.

Streit WJ. Microglia and Alzheimer’s disease pathogenesis.

J Neurosci Res 2004;77:1‑8.

Giulian D. Amoeboid microglia as effectors of inflammation in the

central nervous system. J Neurosci Res 1987;18:155‑71, 132‑3.

Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, et al.

Senile plaques stimulate microglia to release a neurotoxin found

in Alzheimer brain. Neurochem Int 1995;27:119‑37.

Nagata K, Takei N, Nakajima K, Saito H, Kohsaka S. Microglial

conditioned medium promotes survival and development of

cultured mesencephalic neurons from embryonic rat brain.

J Neurosci Res 1993;34:357‑63.

McGeer PL, McGeer EG. The inflammatory response system of brain:

Implications for therapy of Alzheimer and other neurodegenerative

diseases. Brain Res Brain Res Rev 1995;21:195‑218.

McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I,

McGeer EG. Microglia in degenerative neurological disease. Glia

;7:84‑92.

Hanisch UK. Microglia as a source and target of cytokines. Glia

;40:140‑55.

Rice‑Evans CA, Packer L, editors. Flavonoids in health and disease.

New York: Marcel Dekker Inc; 1998.

Hirano T, Oka K, Akibam M. Antiproliferative effect of synthetic

and naturally occurring flavonoids on tumor cells of the human

breast carcinoma cell line, ZR‑75‑1. Res Comm Chem Pathol

Pharmacol 1989;64:69‑79.

Arnold A, Carughi M, Farina G, Merlini L, Parrino MG. Synthetic

analogs of phytoalexins, synthesis and antifungal activity of

potential free radical scavengers. J Agric Food Chem 1989;37:508‑12.

Wacker A, Hilbig W. Virus inhibition by Echinacea purpurea. Planta

Med 1978;33:89‑102.

Stimpel M, Proksch A, Wagner H, Lohmann‑Matthes ML.

Macrophage activation and induction of macrophage cytotoxicity

by purified polysaccharide fractions from the plant Echinacea

purpura. Infect Immun 1984;46:845‑9.

Hertog MGL, Feskens EJ, Hollaman PC, Katan MB, Kromhout D.

Dietary antioxidant flavonoids and risk of coronary heart disease:

the Zutphen elderly study. Lancet 1993;342:1007‑11.

Krieglstein J, Beck T, Seibert A. Influence of an extract of Ginkgo biloba

on cerebral blood flow and metabolism. Life Sci 1986;39:2327‑34.

De Smet PA. Herbal remedies. N Engl J Med 2002;347:2046‑56.

Harvey AL. Medicines from nature: are natural products still

relevant to drug discovery? Trends Pharmacol Sci 1999;20:196‑8.

Ashok AB. The status and scope of Indian medicinal plants acting

on central nervous system. Ind J Pharmacol 1997;29:S340‑3.

Carlini EA. Plants and the central nervous system. Pharmacol

Biochem Behav 2003;75:501‑12.

Howes MJ, Houghton PJ. Plants used in Chinese and Indian

traditional medicine for improvement of memory and cognitive

function. Pharmacol Biochem Behav 2003;75:513‑27.

Shanmuga Sundaram R, Ramanathan M, Gowtham L, Kumar JP,

Bihari CG, Manikandan P, et al. Investigation of standardized

ethanol extract of Ocimum sanctum Linn. (Holy Basil) leaves for

its in vitro antioxidant potential and phenolic composition. Asian

J Chem 2012;24:1819‑24.

Gertz HJ, Kiefer M. Review about Ginkgo biloba special extract EGb

(Ginkgo). Curr Pharm Des 2004;10:261‑4.

Jovanovic SV, Steenken S, Simic MG, Hara Y. Antioxidant

properties of flavonoids: reduction potentials and electron transfer

reactions of flavonoid radicals. In: Rice‑Evans CA, Packer L,

editors. Flavonoids in health and disease. New York: Marcel

Dekker, Inc; 1998. p. 137‑61.

Morel I, Cillard P, Cillard J. Flavonoid‑metal interactions

in biological systems. In: Rice‑Evans CA, Packer L, editors.

Flavonoids in health and disease. New York: Marcel Dekker Inc;

p. 163‑77.

Saija A, Scalese M, Lanza M, Marzullo D, Bonina F, Castelli F.

Flavonoids as antioxidant agents: importance of their interactions

with biomembranes. Free Radic Biol Med 1995;19:481‑6.

Ratty AK, Das NP. Effects of flavonoids on nonenzymatic lipid

peroxidation: structure‑activity relationship. Biochem Med Metab

Biol 1988;39:69‑79.

Kuttan R, Donnely PV, DiFerrante N. Collagen treated with

(1)‑catechin becomes resistant to the action of mammalian

collagenase. Expermentia 1981;37:221‑5.

Robert AM, Godeau G, Moati F, Miskulin M. Action of

anthrocyanosides of vaccinium myrtillis on the permeability of the

blood‑brain barrier. J Med 1977;8:321‑32.

Tzeng SH, Ko WC, Ko FN, Teng CM. Inhibition of platelet

aggregation by some flavonoids. Thromb Res 1991;64:91‑100.

Kim HP, Mani I, Iversen L, Ziboh VA. Effects of naturally occurring

flavonoids and biflavonoids on epidermal cyclooxygenase and

lipooxygenase from guinea pigs. Prostaglandins Leukot Essent

Fatty Acids 1998;58:17‑24.

Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s

disease: Evidence supporting it. Ann Neurol 1992;32:804‑12.

Metodiewa D, Koska C. Reactive oxygen species and reactive

nitrogen species: Relevance to cyto (neuro) toxic events and

neurologic disorders: an overview. Neurotox Res 2000;1:197‑233.

Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba

extract. Cell Mol Life Sci 2003;60:1779‑92.

Kim YO, Leem K, Park J, Lee P, Ahn DK, Lee BC, et al. Cytoprotective

effect of Scutellaria baicalensis in CA1 hippocampal neurons of rats

after global cerebral ischaemia. J Ethnopharmacol 2001;77:183‑8.

Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K. Ginkgo biloba

extract protects brain neurons against oxidative stress induced by

hydrogen peroxide. Brain Res 1996;712:349‑52.

Rahman K. Garlic and aging: new insights into an old remedy.

Ageing Res Rev 2003;2:39‑56.

Lindahl M, Tagesson C. Flavonoids as phospholipase A2 inhibitors:

importance of their structure for selective inhibition of group II

phospholipase A2. Inflammation 1997;21:347‑56.

Pietta P. Flavonoids in medicinal plants. In: Rice‑Evans CA,

Packer L, editors. Flavonoids in health and disease. New York:

Marcel Dekker Inc; 1998. p. 61‑110.

Rohdewald P. Pycnogenol. In: Rice‑Evans CA, Packer L, editors.

Flavonoids in health and disease. New York: Marcel Dekker Inc;

p. 405‑19.

Ben‑Ari Y, Aniksztejn L, Bregestovski P. Protein kinase C

modulation for NMDA currents: an important link for LTP

induction. Trends Neurosci 1992;15:333‑8.

Duthie SJ, Collins AR, Duthie GG, Dobsoin VL. Quercetin and

myricetin protect against hydrogen peroxide‑induced DNA

damage (strand breaks and oxidized pyrimidines) in human

lymphocytes. Mutat Res 1997;393:223‑31.

Griffiths LA. Mammalian metabolism of flavonoids. In:

Harborne JB, Mabry IJ, editors. The flavonoids: advances in

research. London: Chapman and Hall; 1982. p. 681.

Li CL, Werner P, Cohen G. Lipid peroxidation in brain: interaction

of L‑DOPA/dopamine with ascorbate and iron. Neurodegeneration

;4:147‑53.

Afanas’ev BI, Ostrachovitch AE, Abramova EN, Korkina GL.

Different antioxidant activities of bioflavonoid rutin in normal

and iron‑overloading rats. Biochem Pharmacol 1995;50:627‑35.

Dexter DT, Carayon A, Javoy‑Agid F, Agid Y, Wells FR, Daniel SE,

et al. Alterations in the levels of iron, ferritin and other trace metals

in Parkinson’s disease and other neurodegenerative diseases

affecting the basal ganglion. Brain 1991;114:1953‑75.

Kasarskis EJ, Tandon L, Lovell MA, Ehmann WD. Aluminum,

calcium, and iron in the spinal cord of patients with sporadic

amyotrophic lateral sclerosis using laser microprobe mass

spectroscopy: a preliminary study. J Neurol Sci 1995;130:203‑8.

Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, et al.

Structure-activity relationship and classification of flavonoids as

inhibitors of xanthine oxidase and superoxide scavengers. J Nat

Prod 1998;61:71‑6.

Van Acker SA, Tromp MN, Haenen GR, van der Vijgh WJ, Bast A.

Flavonoids as scavengers of nitric oxide radical. Biochem Biophys

Res Comm 1995;214:755‑9.

Schubert D, Kimura H, Maher P. Growth factors and vitamin E

modify neuronal glutamate toxicity. Proc Natl Acad Sci U S A

;89:8264‑8.

Hertog MGL, Katan MB. Quercetin in foods, cardiovascular disease

and cancer. In: Rice‑Evans CA, Packer L, editors. Flavonoids

in health and disease. New York: Marcel Dekker, Inc; 1998.

p. 447‑67.

Tero J, Piskula MK. Flavanoids as inhibitors of lipid peroxidation

in membranes. In: Rice‑Evans CA, Packer L, editors. Flavonoids

in health and disease. New York: Marcel Dekker, Inc; 1998.

p. 277‑93.

Blanc EM, Kelly JF, Mark RJ, Waeg G, Mattson MP.

‑Hydroxynonenal, an aldehyde product of lipid peroxidation,

impairs signal transduction associated with muscarinic

acetylcholine and metabotropic glutamate receptors: possible

actions on G alpha (q/II). J Neurochem 1997;69:570‑80.

Blanc EM, Keller JN, Fernandez S, Mattson MP. 4‑Hydroxynonenal,

a lipid peroxidation product, impairs glutamate transport in

cortical astrocytes. Glia 1998;22:149‑60.

Chromé J, Paul T, Pudel V, Bleyl H, Heseker H, Hppe R, et al. Effect

of suboptimal vitamin status on behavior. In: Somogyi JC, Hotzel

D, editors. Nutrition and neurobiology. New York: Kaeger; 1986.

p. 94‑103.

Sahu SC, Gray GC. Interactions of flavonoids, trace metals and

oxygen: nuclear DNA damage and lipid peroxidation induced by

myricetin. Cancer Lett 1993;70:73‑9.

Sahu SG, Gray GC. Kaempferol‑induced nuclear DNA damage

and lipid peroxidation. Cancer Lett 1994;85:159‑64.

Smith S, Halliwell B, Aruma OI. Protection by albumin against

prooxidant actions of phenolic dietary components. Food Chem

Toxicol 1992;30:483‑9.

Packer L, Saliou C, Droy‑Lefaix MT, Christen Y. Ginkgo biloba extract

Egb 761: biological actions, antioxidant activity, and regulation

of nitric oxide synthetase. In: Rice‑Evans CA, Packer L, editors.

Flavonoids in health and disease. New York: Marcel Dekker, Inc;

p. 303‑41.

Yoneda T, Hiramatsu M, Sakamoto M, Togasaki K, Komatsu M,

Yamaguchi K. Antioxidant effects of beta catechins. Biochem Mol

Biol Int 1995;35:995‑1008.

Rohdewald P. Pycnogenol. In: Rice‑Evans CA, Packer L, editors.

Flavonoids in health and disease. New York: Marcel Dekker, Inc;

p. 405‑19.

Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide

mediates amyloidal beta‑protein toxicity. Cell 1994;77:817‑27.

Schubert D, Kimurah H, Maher P. Growth factors and vitamin E

modify neuronal glutamate toxicity. Proc Natl Acad Sci U S A

;89:8264‑8.

Scheibel AB, Duong T. On the possible relationship of cortical

microvascular pathology to blood‑brain barrier changes in

Alzheimer’s disease. Neurobiol Aging 1988;9:41‑2.

Grotemeyer KH. The platelet‑reactivity test‑ a useful by‑product

of blood sampling procedure. Thromb Res 1991;61:423‑31.

Demrow HS, Slane PR, Folts JD. Administration of wine and grape

juice inhibits in vivo platelet activity and thrombosis in stenosed

cainine coronary arteries. Circulation 1995;91:1182‑8.

Shanmuga Sundaram R, Ramanathan M, Rajesh R, Satheesh B,

Saravanan D. LC‑MS quantification of rosmarinic acid and ursolic

acid in the Ocimum sanctum Linn. leaf extract (Holy basil, Tulsi).

J Liq Chromatogr Relat Technol 2012;35:634‑50.

Shanmuga Sundaram R, Gowtham L, Manikandan P,

Venugopal V, Kamalakannan D. The role of reactive microglia

in neurodegenerative disease: Multiple triggers with a common

mechanism. Int J Recent Adv Pharm Res 2012;2:29‑40.

Shanmuga Sundaram R, Gowtham L, Bhabani SN. The role of

excitatory neurotransmitter glutamate in brain physiology and

pathology. Asian J Pharm Clin Res 2012;5:1‑7.

Shanmuga Sundaram R, Gowtham L, Manikandan P, Venugopal V,

Kamalakannan D. Neuronal apoptosis and necrosis: role of

excitotoxins, calcium, oxidative stress. Int J Res Pharm Biomed

Sci 2012;3:567‑75.

Lolic MM, Fiskum G, Rosenthal RE. Neuroprotective effects

of acetyl‑L‑carnitine after stroke in rats. Ann Emerg Med 1997;

:758–65.

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