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Spontaneously hypertensive rat as a model of vascular brain disorder: Microanatomy, neurochemistry and behavior

      Abstract

      Arterial hypertension is the main risk factor for stroke and plays a role in the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). An association between hypertension and reduced cerebral blood flow and VCI is documented and arterial hypertension in midlife is associated with a higher probability of cognitive impairment. These findings suggest that arterial hypertension is a main cause of vascular brain disorder (VBD).
      Spontaneously hypertensive rat (SHR) is the rat strain most extensively investigated and used for assessing hypertensive brain damage and treatment of it. They are normotensive at birth and at 6 months they have a sustained hypertension. Time-dependent rise of arterial blood pressure, the occurrence of brain atrophy, loss of nerve cells and glial reaction are phenomena shared to some extent with hypertensive brain damage in humans.
      SHR present changes of some neurotransmitter systems that may have functional and behavioral relevance. An impaired cholinergic neurotransmission characterizes SHR, similarly as reported in patients affected by VaD. SHR are also characterized by a dopaminergic hypofunction and noradrenergic hyperactivity similarly as occurs in attention-deficit with hyperactivity disorder (ADHD).
      Microanatomical, neurochemical and behavioral data on SHR are in favor of the hypothesis that this strain is a suitable model of VBD. Changes in catecholaminergic transmission put forward SHR as a possible model of ADHD as well. Hence SHR could represent a multi-faced model of two important groups of pathologies, VBD and ADHD. As for most models, researchers should always consider that SHR offer some similarities with corresponding human pathologies, but they do not suffer from the same disease.
      This paper reviews the main microanatomical, neurochemical and behavioral characteristics of SHR with particular reference as an animal model of brain vascular injury.

      Keywords

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      References

        • Folkow B.
        Physiological aspects of primary hypertension.
        Physiol Rev. 1982; 62: 347-504
        • Meneses A.
        • Castillo C.
        • Ibarra M.
        • Hong E.
        Effects of aging and hypertension on learning, memory and activity in rats.
        Physiol Behav. 1996; 60: 341-345
        • Meneses A.
        • Terro'n J.A.
        • Ibarra M.
        • Hong E.
        Effects of nimodipine on learning in normotensive and spontaneously hypertensive rats.
        Behav Brain Res. 1997; 85: 121-125
        • Meneses A.
        • Hong E.
        Spontaneously hypertensive rats a potential model to identify drugs for treatment of learning disorders.
        Hypertension. 1998; 31: 968-972
        • Okamoto K.
        • Aoki K.
        Development of a strain of spontaneously hypertensive rats.
        Jpn Circ J. 1964; 27: 282-292
        • Sabbatini M.
        • Strocchi P.
        • Vitaioli L.
        • Amenta F.
        Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovascular disease of the elderly.
        Mech Ageing Dev. 2001; 122: 1257-1268
        • Leoni R.F.
        • Paiva F.F.
        • Henning E.C.
        • Nascimento G.C.
        • Tannús A.
        • de Araujo D.B.
        • et al.
        Magnetic resonance imaging quantification of regional cerebral blood flow and cerebrovascular reactivity to carbon dioxide in normotensive and hypertensive rats.
        Neuroimage. 2011; 58: 75-81
        • Light K.C.
        Slowing response time in young and middle-aged hypertensive patients.
        Exp Aging Res. 1975; 1: 209-227
        • Light K.C.
        Effects of mild cardiovascular and cerebrovascular disorders on serial reaction time performance.
        Exp Aging Res. 1978; 4: 3-22
        • Schultz Jr., N.R.
        • Dineen J.T.
        • Pentz III, C.A.
        • Wood W.G.
        WAIS performance for different age groups of hypertensive and control subjects during the administration of a diuretic.
        J Gerontol. 1979; 34: 246-253
        • Battersby G.
        • Hartley K.
        • Fletcher A.E.
        • Markowe H.J.L.
        • Brown R.G.
        • Styles W.
        • et al.
        Cognitive function in hypertension: a community based study.
        J Hum Hypertens. 1993; 7: 117-123
        • Elias M.F.
        • Wolf P.A.
        • D'Agostino R.B.
        • Janet Cobb C.
        • White L.R.
        Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study.
        Am J Epidemiol. 1993; 138: 353-364
        • Karla L.
        • Jackson S.H.D.
        • Swift C.G.
        Psychomotor performance in elderly hypertensive patients.
        J Hum Hypertens. 1993; 7: 279-284
        • Launer L.J.
        • Masaki K.
        • Petrovitch H.
        • Foley D.
        • Havlik R.J.
        The association between midlife blood pressure levels and late-life cognitive function.
        J Am Med Assoc. 1995; 274: 1846-1851
        • Shapiro A.P.
        • Miller R.E.
        • King H.E.
        • Ginchereau E.H.
        • Fitzgibbon K.
        Behavioral consequences of mild hypertension.
        Hypertension. 1982; 4: 355-360
        • Waldstein S.R.
        • Ryan C.M.
        • Manuck S.B.
        • Parkinson D.K.
        • Bromet E.J.
        Learning and memory function in men with untreated blood pressure elevation.
        J Consult Clin Psychol. 1991; 5: 513-517
        • Hecht K.
        • Poppei M.
        • Hecht T.
        • Postnow J.W.
        • Moritz V.
        • Baumann R.
        Lern- und Gedachtnissprozesse wahrend der postnatalen ontogonese von Ratten mit spontaner hypertonie.
        Acta Biol Med. 1978; 37: 147-178
        • Jr Sutterer
        • Perry J.
        • De Vito W.
        Two-way shuttle box and leverpress avoidance in the spontaneously hypertensive and normotensive rat.
        J Comp Physiol Psychol. 1980; 9: 155-163
        • Mori S.
        • Kato M.
        • Fujishima M.
        Impaired maze learning and cerebral glucose utilization in aged hypertensive rats.
        Hypertension. 1995; 25: 545-553
        • Wyss J.M.
        • Fisk G.
        • Groen T.V.
        Impaired learning and memory in mature spontaneously hypertensive rats.
        Brain Res. 1992; 592: 135-140
        • Campbell R.J.
        • Di Cara L.V.
        Running wheel avoidance behavior in the Wistar Kyoto and spontaneously hypertensive rat.
        Physiol Behav. 1977; 19: 473-480
        • Randich A.
        • Maxiner W.
        Acquisition of conditioned suppression and responsivity to thermal stimulation in spontaneously hypertensive, renal hypertensive and normotensive rats.
        Physiol Behav. 1981; 27: 585-590
        • Knardahl S.
        • Sagvolden T.
        Two-way active avoidance behavior of spontaneously hypertensive rats: effect of intensity of discontinuous shock.
        Behav Neural Biol. 1982; 35: 105-120
        • Widy-Tyszkiewicz E.
        • Scheel-Kruger J.
        • Christensen A.V.
        Spatial navigation learning in spontaneously hypertensive, renal hypertensive and normotensive Wistar rats.
        Behav Brain Res. 1993; 54: 179-185
        • Andersson K.
        • Post B.
        Effects of cigarette smoking on verbal note learning and physiological arousa.
        Scand J Psychol. 1974; 15: 263-267
        • Houston J.P.
        • Schneider N.G.
        • Jarvik M.E.
        Effects of smoking on free recall and organization.
        Am J Psychiatry. 1978; 135: 220-222
        • Warburton D.M.
        • Wesnes K.
        • Shergold K.
        • James M.
        Facilitation of learning and state dependency with nicotine.
        Psychopharmacology. 1986; 89: 55-59
        • West R.
        • Hack S.
        Effect of cigarettes on memory search and subjective ratings.
        Pharmacol Biochem Behav. 1991; 38: 281-286
        • Buccafusco J.J.
        • Jackson W.J.
        Beneficial effects of nicotine administered prior to a delayed matching-to-sample task in young and aged monkeys.
        Neurobiol Aging. 1991; 12: 233-238
        • Elrod K.
        • Buccafusco J.J.
        • Jackson W.J.
        Nicotine enhances delayed matching-to-sample performance by primates.
        Life Sci. 1988; 43: 277-287
        • Jackson W.J.
        • Elrod K.
        • Buccafusco J.J.
        Delayed matching-to-sample in monkeys as a model for learning and memory deficits: role of brain nicotinic receptors.
        in: Meyer E.M. Simpkins J.W. Yamamoto J. Novel approaches to the treatment of Alzheimer's disease. Plenum Press, New York1989: 39-52
        • Levin E.D.
        • Lee C.
        • Rose J.E.
        • Reyes A.
        • Ellison G.
        • Jaravik M.
        • et al.
        Chronic nicotine and withdrawal effects on radial arm maze performance in rats.
        Behav Neural Biol. 1990; 53: 269-276
        • Levin E.D.
        Nicotinic systems and cognitive function.
        Psychopharmacology. 1992; 108: 417-431
        • Khan I.M.
        • Printz M.P.
        • Yakash T.L.
        • Taylor P.
        Augmented response to intrathecal nicotinic agonists in spontaneous hypertension.
        Hypertension. 1994; 24: 611-619
        • Kubo T.
        • Misu Y.
        Cardiovascular response to microinjection of physostigmine and choline into the dorsal medullary site of the rat.
        Neuropharmacology. 1981; 20: 1091-1095
        • Yamada S.
        • Kagawa Y.
        • Ushijima H.
        • Takayanagi N.
        • Tomita T.
        • Hayashi E.
        Brain nicotinic cholinoceptor binding in spontaneous hypertension.
        Brain Res. 1987; 410: 212-218
        • Gattu M.
        • Pauly J.R.
        • Boss K.L.
        • Summers J.B.
        • Buccafusco J.J.
        Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. Part I.
        Brain Res. 1997; 771: 89-103
        • Gattu M.
        • Terry Jr., A.V.
        • Pauly J.R.
        • Buccafusco J.J.
        Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors.
        Part II. Brain Res. 1997; 771: 104-114
        • Li M.
        • Bertout J.A.
        • Ratcliffe S.J.
        • Eckenhoff M.F.
        • Simon M.C.
        • Floyd T.F.
        Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension.
        Anesthesiology. 2010; 113: 845-858
        • Wyss J.M.
        • Chambless B.D.
        • Kadish I.
        • van Groen T.
        Age-related decline in water maze learning and memory in rats: strain differences.
        Neurobiol Aging. 2000; 21: 671-681
        • van der Staay F.J.
        • de Jonge M.
        Effects of age on water escape behavior and on repeated acquisition in rats.
        Behav Neural Biol. 1993; 60: 33-41
        • Hong E.
        • Ibarra M.
        • Meneses A.
        • Ransanz V.
        • CastiUo C.
        Effects of hypertension and ageing on vascular reactivity and associative learning.
        Proc West Pharmacol Soc. 1992; 35: 183-185
        • Goldstein G.
        • Materson B.I.
        • Cushman W.C.
        • et al.
        Treatment of hypertension in the elderly: II. Cognitive and behavioral function.
        Hypertension. 1990; 15: 361-369
        • Meneses A.
        • Castillo C.
        • Ibarra M.
        • Hong E.
        Effects of aging and hypertension on learning, memory, and activity in rats.
        Physiol Behav. 1996; 60: 341-345
        • Sagvolden T.
        • Wultz B.
        • Moser E.I.
        • Moser M.B.
        • Morkid L.
        Future perspective on ADD research: an irresistible challenge.
        in: Sagvolden T. Archer T. Attention deficits disorder: clinical and basic research. Lawrence Erlbaum, Hillsdale, NJ1989: 261-286
        • Sagvolden T.
        • Hendley E.D.
        • Knardahl S.
        Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined.
        Physiol Behav. 1992; 52: 49-57
        • Svensson L.
        • Harthon C.
        • Linder B.
        Evidence for a dissociation between cardiovascular and behavioral reactivity in the spontaneously hypertensive rat.
        Physiol Behav. 1991; 49: 661-665
        • Soderpalm B.
        The SHR exhibits less “anxiety” but increased sensitivity to the anticonflict effect of clonidine compared to normotensive control.
        Pharmacol Toxicol. 1989; 65: 381-386
        • Turkkan J.S.
        Behavioral performance effects of antihypertensive drugs: human and animals studies.
        Neurosci Biobehav Rev. 1988; 12: 111-122
        • Wultz B.
        • Sagvolden T.
        • Moser E.I.
        • Moser M.B.
        The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior.
        Behav Neural Biol. 1990; 53: 88-102
        • Dourish C.T.
        Effects of drugs on spontaneous motor activity.
        in: Greenshaw A.J. Dourish C.T. Experimental psychopharmacology. Humana Press, Clifton NJ1987: 153-211
        • Bianchi G.
        • Ferrari P.
        • Barber B.R.
        Lessons from experimental genetic hypertension.
        in: Laragh J.H. Brenner B.M. Hypertension: pathophysiology, diagnosis and management. Raven Press, New York1990: 901-922
        • Docherty J.R.
        Cardiovascular responses in ageing: a review.
        Pharmacol Rev. 1990; 42: 103-125
        • Elias M.F.
        • Robbins M.A.
        • Schultz N.R.
        • Streeten D.H.
        • Elias P.K.
        Clinical significance of cognitive performance by hypertensive patients.
        Hypertension. 1987; 9: 192-197
        • Goldstein G.
        • Materson B.I.
        • Cushman W.C.
        • et al.
        Treatment of hypertension in the elderly: II. Cognitive and behavioral function.
        Hypertension. 1990; 15: 361-369
        • Johansson B.B.
        Cerebral vascular bed in hypertension and consequences for the brain.
        Hypertension. 1984; 6: 81-86
        • Lindholm L.
        Hypertension and ageing.
        Clin Exp Theor Pract. 1990; A12: 745-759
        • Wyss J.M.
        • Franklin J.A.
        • van Groen T.
        Impaired learning and memory in mature and old spontaneously hypertensive and Wistar–Kyoto rats.
        Soc Neurosci Abstr. 1994; 20: 1216
        • Smith T.L.
        • Hutchins P.M.
        Central hemodynamics in the developmental stage of spontaneous hypertension in the unanesthetized rat.
        Hypertension. 1979; 1: 508-517
        • Faraci F.M.
        • Heistad D.D.
        Regulation of large cerebral arteries and cerebral microvascular pressure.
        Circ Res. 1990; 66: 8-17
        • Welch K.M.A.
        • Caplan L.R.
        • Reis D.J.
        • Siesjo¨ D.J.
        • Weir B.
        Primer on cerebrovascular diseases.
        Academic Press, New York1997
        • Edvinsson L.
        • MacKenzie E.T.
        • McCulloch J.
        Cerebral blood flow and metabolism.
        Raven Press, New York1993
        • Fredriksson K.
        • Nordborg C.
        • Johansson B.B.
        The hemodynamic effect of bilateral carotid ligation and the morphometric characteristics of the main communicating circuit in normotensive and spontaneously hypertensive rats.
        Acta Physiol Scand. 1984; 121: 241-247
        • Johansson B.B.
        • Fredriksson K.
        Cerebral arteries in hypertension: structural and hemodynamic aspects.
        J Cardiovasc Pharmacol. 1985; 7: 90-93
        • Heagerty A.M.
        • Aalkjaer C.
        • Bund S.J.
        • Korsgaard N.
        • Mulvany M.J.
        Small artery structure in hypertension. Dual processes of remodelling and growth.
        Hypertension. 1993; 21: 391-397
        • Mulvany M.J.
        Resistance vessel structure and the pathogenesis of hypertension.
        J Hypertens. 1993; : S7-S12
        • Amenta F.
        • Strocchi P.
        • Sabbatini M.
        Vascular and neuronal hypertensive brain damage: protective effect of treatment with nicardipine.
        J Hypertens. 1996; : S29-S35
        • Lee R.M.
        • Smeda J.S.
        Primary versus secondary structural changes of the blood vessels in hypertension.
        Can J Physiol Pharmacol. 1985; 63: 392-401
        • Folkow B.
        • Hallbäck M.
        • Lundgren Y.
        • Sivertsson R.
        • Weiss L.
        Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats.
        Circ Res. 1973; 32: 2-16
        • Baumbach G.L.
        • Heistad D.D.
        Effects of sympathetic stimulation and changes in arterial pressure on segmental resistance of cerebral vessels in rabbits and cats.
        Circ Res. 1983; 52: 527-533
        • Schilling L.
        • Wahl M.
        Brain edema: pathogenesis and therapy.
        Kidney Int. 1997; 59: S69-S75
        • Mueller S.M.
        • Heistad D.D.
        Effect of chronic hypertension on the blood–brain barrier.
        Hypertension. 1980; 2: 809-812
        • Al-Sarraf H.
        • Philip L.
        Effect of hypertension on the integrity of blood brain and blood CSF barriers, cerebral blood flow and CSF secretion in the rat.
        Brain Res. 2003; 975: 179-188
        • Nielsen S.
        • Nagelhus E.A.
        • Amiry-Moghaddam M.
        • Bourque C.
        • Agre P.
        • Ottersen O.P.
        Specialized membrane domains for water transport in glial cells: high resolution immunogold cytochemistry of aquaporin-4 in rat brain.
        J Neurosci. 1997; 17: 171-180
        • Rash J.E.
        • Yasumura T.
        • Hudson C.S.
        • Agre P.
        • Nielsen S.
        Direct immunogold labelling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord.
        Proc Natl Acad Sci U S A. 1998; 95: 11981-11986
        • Saadoun S.
        • Papadopoulos M.
        • Bell B.
        • Krishna S.
        • Davies D.
        The aquaporin-4 water channel and brain tumour oedema.
        J Anat. 2002; 200: 528
        • Vizuete M.L.
        • Venero J.L.
        • Vargas C.
        • Ilundáin A.A.
        • Echevarría M.
        • Machado A.
        • et al.
        Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema.
        Neurobiol Dis. 1999; 6: 245-258
        • Ke C.
        • Poon W.S.
        • Ng H.K.
        • Pang J.C.
        • Chan Y.
        Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats.
        Neurosci Lett. 2001; 301: 21-24
        • Taniguchi M.
        • Yamashita T.
        • Kumura E.
        • et al.
        Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat.
        Brain Res Mol Brain Res. 2000; 78: 131-137
        • Vajda Z.
        • Promeneur D.
        • Dóczi T.
        • et al.
        Increased aquaporin-4 immunoreactivity in rat brain in response to sistemi hyponatremia.
        Biochem Biophys Res Commun. 2000; 270: 495-503
        • Ritter S.
        • Dinh T.T.
        Progressive postnatal dilation of brain ventricles in spontaneously hypertensive rats.
        Brain Res. 1986; 370: 327-332
        • Tajima A.
        • Hans F.J.
        • Livingstone D.
        • Wei L.
        • et al.
        Smaller local brain volumes and cerebral atrophy in spontaneously hypertensive rats.
        Hypertension. 1993; 21: 105-111
        • Nelson D.O.
        • Boulant J.A.
        Altered CNS neuroanatomical organization of spontaneously hypertensive (SHR) rats.
        Brain Res. 1981; 226: 119-130
        • Sabbatini M.
        • Baldoni E.
        • Cadoni A.
        • Vitaioli L.
        • Zicca A.
        • Amenta F.
        Forebrain white matter in spontaneously hypertensive rats: a quantitative image analysis study.
        Neurosci Lett. 1999; 265: 5-8
        • Lehr Jr., R.P.
        • Browning R.A.
        • Myers J.H.
        Gross morphological brain differences between Wistar–Kyoto and spontaneously hypertensive rats.
        Clin Exp Hypertens. 1980; 2: 123-127
        • Sabbatini M.
        • Tomassoni D.
        • Amenta F.
        Hypertensive brain damage: comparative evaluation of protective effect to treatment with dihydropyridine derivatives in spontaneously hypertensive rats.
        Mech Ageing Dev. 2001; 122: 2085-2105
        • Lanari A.
        • Silvestrelli G.
        • De Dominicis P.
        • Tomassoni D.
        • Amenta F.
        • Parnetti L.
        Arterial hypertension and cognitive dysfunction in physiologic and pathologic aging of the brain.
        Am J Geriatr Cardiol. 2007; 16: 158-164
        • Li Q.
        • Lu G.
        • Antonio G.E.
        • Mak Y.T.
        • Rudd J.A.
        • Fan M.
        • et al.
        The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain.
        Neurochem Int. 2007; 50: 848-857
        • Bendel P.
        • Eilam R.
        Quantitation of ventricular size in normal and spontaneously hypertensive rats by magnetic resonance imaging.
        Brain Res. 1992; 574: 224-228
        • Sabbatini M.
        • Strocchi P.
        • Vitaioli L.
        • Amenta F.
        The hippocampus in spontaneously hypertensive rats: a quantitative microanatomical study.
        Neuroscience. 2000; 100: 251-258
        • Sabbatini M.
        • Catalani A.
        • Consoli C.
        • Marletta N.
        • Tomassoni D.
        • Avola R.
        The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia?.
        Mech Ageing Dev. 2002; 123: 547-559
        • Johansson B.B.
        Pentoxifylline: cerebral blood flow and glucose utilization in conscious spontaneously hypertensive rats.
        Stroke. 1986; 17: 744-747
        • Wei L.
        • Lin S.Z.
        • Tajima A.
        • Nakata H.
        • Acuff V.
        • Patlak C.
        • et al.
        Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats.
        Hypertension. 1992; 20: 501-510
        • Grabowski M.
        • Nordborg C.
        • Brundin P.
        • Johansson B.B.
        Middle cerebral artery occlusion in the hypertensive and normotensive rat: a study of histopathology and behaviour.
        J Hypertens. 1988; 6: 405-411
        • Breteler M.M.
        • van Amerongen N.M.
        • van Swieten J.C.
        • et al.
        Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging. The Rotterdam study.
        Stroke. 1994; 25: 1109-1115
        • Pantoni L.
        • Garcia J.H.
        Cognitive impairment and cellular/vascular changes in the cerebral white matter.
        Ann N Y Acad Sci. 1997; 826: 92-102
        • Englund E.
        Neuropathology of white matter changes in Alzheimer's disease and vascular dementia.
        Dement Geriatr Cogn Disord. 1998; 9: 6-12
        • Schmidt R.
        • Mechtler L.
        • Kinkel P.R.
        • Fazekas F.
        • Kinkel W.R.
        • Freidl W.
        Cognitive impairment after acute supratentorial stroke: a 6-month follow-up clinical and computed tomographic study.
        Eur Arch Psychiatry Clin Neurosci. 1993; 243: 11-15
        • Tomassoni D.
        • Baldoni E.
        • Di Tullio M.A.
        • Avola R.
        • Vitaioli L.
        Glial reaction in brain white matter of spontaneously hypertensive rats.
        Ital J Anat Embryol. 2002; 109: 146
        • Lin J.X.
        • Tomimoto H.
        • Akiguchi I.
        • Wakita H.
        • Shibasaki H.
        • Horie R.
        White matter lesions and alteration of vascular cell composition in the brain of spontaneously hypertensive rats.
        Neuroreport. 2001; 12: 1835-1839
        • Muñoz-Fernández M.A.
        • Fresno M.
        The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system.
        Prog Neurobiol. 1998; 56: 307-340
        • Fu K.Y.
        • Light A.R.
        • Matsushima G.K.
        • Maixner W.
        Microglial reactions after subcutaneous formalin injection into the rat hind paw.
        Brain Res. 1999; 825: 59-67
        • Masumura M.
        • Hata R.
        • Nagai Y.
        • Sawada T.
        Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats.
        Neurosci Res. 2001; 39: 401-412
        • Ridet J.L.
        • Malhotra S.K.
        • Privat A.
        • Gage F.H.
        Reactive astrocytes: cellular and molecular cues to biological function.
        Trends Neurosci. 1997; 20: 570-577
        • Holash J.A.
        • Noden D.M.
        Stewart PARe-evaluating the role of astrocytesin blood–brain barrier induction.
        Dev Dyn. 1993; 97: 14-25
        • Müller C.M.
        A role for glial cells in activity-dependent central nervous plasticity? Review and hypothesis.
        in: Bradley R.J. International review of neurobiology. Academic Press, San Diego, CA1992: 215-281
        • Janeczko K.
        Co-expression of GFAP and vimentin in astrocytes proliferating in response to injury in the mouse cerebral hemisphere. A combined autoradiographic and double immunocytochemical study.
        Int J Dev Neurosci. 1993; 11: 139-147
        • Liedtke W.
        • Edelmann W.
        • Bieri P.L.
        • et al.
        GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination.
        Neuron. 1996; 17: 607-615
        • McCall M.A.
        • Gregg R.G.
        • Behringer R.R.
        • et al.
        Targeted deletion in astrocyte intermediate filament (GFAP) alters neuronal physiology.
        Proc Natl Acad Sci U S A. 1996; 93: 6361-6366
        • Gimenez M.A.
        • Sim J.E.
        • Russell J.H.
        TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation.
        J Neuroimmunol. 2004; 151: 116-125
        • Nawashiro H.
        • Brenner M.
        • Fukui S.
        • Shima K.
        • Hallenbeck J.M.
        High susceptibility to cerebral ischemia in GFAP-null mice.
        J Cereb Blood Flow Metab. 2000; 20: 1040-1044
        • Fernaud-Espinosa I.
        • Nieto-Sampedro M.
        • Bovolenta P.
        Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue.
        Glia. 1993; 8: 277-291
        • Nichols N.R.
        • Day J.R.
        • Laping N.J.
        • Johnson S.A.
        • Finch C.E.
        GFAP mRNA increases with age in rat and human brain.
        Neurobiol Aging. 1993; 14: 421-429
        • Linnemann D.
        • Skarsfelt T.
        Regional changes in expression of NCAM, GFAP, and S100 in aging rat brain.
        Neurobiol Aging. 1994; 15: 651-655
        • Cheung W.M.
        • Wang C.K.
        • Kuo J.S.
        • Lin T.N.
        Changes in the level of glial fibrillary acidic protein (GFAP) after mild and severe focal cerebral ischemia.
        Chin J Physiol. 1999; 42: 227-235
        • Catalani A.
        • Sabbatini M.
        • Consoli C.
        • Cinque C.
        • Tomassoni D.
        • Azmitia E.
        • et al.
        Glial fibrillary acidic protein immunoreactive astrocytes in developing rat hippocampus.
        Mech Ageing Dev. 2002; 123: 481-490
        • Unger J.W.
        Glial reaction in aging and Alzheimer's disease.
        Microsc Res Tech. 1998; 43: 24-28
        • Kristjánsdóttir R.
        • Uvebrant P.
        • Rosengren L.
        Glial fibrillary acidic protein and neurofilament in children with cerebral white matter abnormalities.
        Neuropediatrics. 2001; 32: 307-312
        • Tomassoni D.
        • Avola R.
        • Di Tullio M.A.
        • Sabbatini M.
        • Vitaioli L.
        • Amenta F.
        Increased expression of glial fibrillary acidic protein in the brain of spontaneously hypertensive rats.
        Clin Exp Hypertens. 2004; 26: 335-350
        • Tomassoni D.
        • Avola R.
        • Mignini F.
        • Parnetti L.
        • Amenta F.
        Effect of treatment with choline alphoscerate on hippocampus microanatomy and glial reaction in spontaneously hypertensive rats.
        Brain Res. 2006; 1120: 183-190
        • Amenta F.
        • Tayebati S.K.
        Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.
        Curr Med Chem. 2008; 15: 488-498
        • Gottfries C.G.
        • Blennow K.
        • Karlsson I.
        • Wallin A.
        The neurochemistry of vascular dementia.
        Dementia. 1994; 5: 163-167
        • Hernandez C.M.
        • Høifødt H.
        • Terry Jr., A.V.
        Spontaneously hypertensive rats: further evaluation of age-related memory performance and cholinergic marker expression.
        J Psychiatry Neurosci. 2003; 28: 197-209
        • Buccafusco J.J.
        The role of central cholinergic neurons in the regulation of blood pressure and in experimental hypertension.
        Pharmacol Rev. 1996; 48: 179-211
        • Kubo T.
        Cholinergic mechanism and blood pressure regulation in the central nervous system.
        Brain Res Bull. 1998; 46: 475-481
        • Helke C.J.
        • Muth E.A.
        • Jacobowitz D.M.
        Changes in central cholinergic neurons in the spontaneously hypertensive rat.
        Brain Res. 1980; 188: 425-436
        • Togashi H.
        • Matsumoto M.
        • Yoshioka M.
        • Hirokami M.
        • Minami M.
        • Saito H.
        Neurochemical profiles in cerebrospinal fluid of stroke-prone spontaneously hypertensive rats.
        Neurosci Lett. 1994; 166: 117-120
        • Saito H.
        • Togashi H.
        • Yoshioka M.
        • Nakamura N.
        • Minami M.
        • Parvez H.
        Animal models of vascular dementia with emphasis on strokeprone spontaneously hypertensive rats.
        Clin Exp Pharmacol Physiol. 1995; : S257-S259
        • Kimura S.
        • Saito H.
        • Minami M.
        • et al.
        Pathogenesis of vascular dementia in strokeprone spontaneously hypertensive rats.
        Toxicology. 2000; 153: 167-178
        • Togashi H.
        • Kimura S.
        • Matsumoto M.
        • Yoshioka M.
        • Minami M.
        • Saito H.
        Cholinergic changes in the hippocampus of stroke-prone spontaneously hypertensive rats.
        Stroke. 1996; 27: 520-525
        • Tayebati S.K.
        • Di Tullio M.A.
        • Amenta F.
        Effect of treatment with the cholinesterase inhibitor rivastigmine on vesicular acetylcholine transporter and choline acetyltransferase in rat brain.
        Clin Exp Hypertens. 2004; 26: 363-373
        • Tayebati S.K.
        • Di Tullio M.A.
        • Amenta F.
        Vesicular acetylcholine transporter (VAChT) in the brain of spontaneously hypertensive rats (SHR): effect of treatment with an acetylcholinesterase inhibitor.
        Clin Exp Hypertens. 2008; 30: 732-743
        • Hu L.
        • Wong T.P.
        • Cote S.L.
        • Bell K.F.
        • Cuello A.C.
        The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in Alzheimer's disease-like transgenic mice.
        Neuroscience. 2003; 121: 421-432
        • DeKosky S.T.
        • Ikonomovic M.D.
        • Styren S.D.
        • Beckett L.
        • Wisniewski S.
        • Bennett D.A.
        • et al.
        Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.
        Ann Neurol. 2002; 51: 145-155
        • DeKosky S.T.
        • Ikonomovic M.D.
        • Styren S.D.
        • et al.
        Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.
        Ann Neurol. 2002; 51: 143-144
        • Knardahl S.
        • Karlsen K.
        Passive avoidance behavior of spontaneously hypertensive rats.
        Behav Neural Biol. 1984; 42: 9-22
        • Tayebati S.K.
        • Di Tullio M.A.
        • Tomassoni D.
        • Amenta F.
        Neuroprotective effect of treatment with galantamine and choline alphoscerate on brain microanatomy in spontaneously hypertensive rats.
        J Neurol Sci. 2009; 283: 187-194
        • Tayebati S.K.
        • Tomassoni D.
        • Di Stefano A.
        • Sozio P.
        • Cerasa L.S.
        • Amenta F.
        Effect of choline-containing phospholipids on brain cholinergic transporters in the rat.
        J Neurol Sci. 2011; 302: 49-57
        • Tomassoni D.
        • Catalani A.
        • Cinque C.
        • Di Tullio M.A.
        • Tayebati S.K.
        • Cadoni A.
        • et al.
        Effects of cholinergic enhancing drugs on cholinergic transporters in the brain and peripheral blood lymphocytes of spontaneously hypertensive rats.
        Curr Alzheimer Res. 2012; 9: 120-127
        • Russell V.A.
        Reprint of “Neurobiology of animal models of attention-deficit hyperactivity disorder”.
        J Neurosci Methods. 2007; 166: I-XIV
        • Carboni E.
        • Silvagni A.
        • Valentini V.
        • Di Chiara G.
        Effect of amphetamine, cocaine and depolarization by high potassium on extracellular dopamine in the nucleus accumbens shell of SHR rats. An in vivo microdyalisis study.
        Neurosci Biobehav Rev. 2003; 27: 653-659
        • de Villiers A.S.
        • Russell V.A.
        • Sagvolden T.
        • Searson A.
        • Jaffer A.
        • Taljaard J.J.
        Alpha 2-adrenoceptor mediated inhibition of [3H] dopamine release from nucleus accumbens slices and monoamine levels in a rat model for attention-deficit hyperactivity disorder.
        Neurochem Res. 1995; 20: 427-433
        • Printz M.P.
        • Jirout M.
        • Jaworski R.
        • Alemayehu A.
        • Kren V.
        Genetic models in applied physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics.
        J Appl Physiol. 2003; 94: 2510-2522
        • Tsukamoto K.
        • Sved A.F.
        • Ito S.
        • Komatsu K.
        • Kanmatsuse K.
        Enhanced serotoninmediated responses in the nucleus tractus solitarius of spontaneously hypertensive rats.
        Brain Res. 2000; 863: 1-8
        • Sakurai-Yamashita Y.
        • Yamashita K.
        • Niwa M.
        • Taniyama K.
        Involvement of 5-hydroxytryptamine4 receptor in the exacerbation of neuronal loss by psychological stress in the hippocampus of SHRSP with a transient ischemia.
        Brain Res. 2003; 973: 92-98