{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T09:14:36Z","timestamp":1774084476296,"version":"3.50.1"},"reference-count":48,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1989,7]]},"abstract":"<jats:p content-type=\"fine-print\">\u2713 Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run an eight-arm radial maze, after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however, displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p &lt; 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.<\/jats:p>","DOI":"10.3171\/jns.1989.71.1.0105","type":"journal-article","created":{"date-parts":[[2009,5,8]],"date-time":"2009-05-08T16:21:09Z","timestamp":1241799669000},"page":"105-112","source":"Crossref","is-referenced-by-count":62,"title":["Intracerebral drug delivery in rats with lesion-induced memory deficits"],"prefix":"10.3171","volume":"71","author":[{"given":"Matthew A.","family":"Howard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Gross","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Sean","family":"Grady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Langer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith","family":"Mathiowitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. Richard","family":"Winn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc R.","family":"Mayberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"key":"b1","series-title":"Brain Res Bull","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/0361-9230(82)90101-0","article-title":"Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis.","volume":"8","author":"Bigl","year":"1982"},{"key":"b2","series-title":"Neurobiol Aging","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/0197-4580(86)90010-2","article-title":"Number of neurons in nucleus locus ceruleus in demented and nondemented patients: rapid estimation and correlated parameters.","volume":"7","author":"Bondareff","year":"1986"},{"key":"b3","series-title":"Prog Neuropsychopharmacol Biol Psychiatry","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0278-5846(86)90007-2","article-title":"Neuropeptides in Alzheimer's disease: a review and morphological results.","volume":"10","author":"Bouras","year":"1986"},{"key":"b4","series-title":"J Comp Neurol","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1002\/cne.902500206","article-title":"Ultrastructural organization of choline-acetyltransferase-immunoreactive fibers innervating the neocortex from embryonic ventral forebrain grafts.","volume":"250","author":"Clarke","year":"1986"},{"key":"b5","series-title":"J Comp Neurol","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/cne.902520405","article-title":"Grafted septal neurons from cholinergic synaptic connections in the dentate gyrus of behaviorally impaired aged rats.","volume":"252","author":"Clarke","year":"1986"},{"key":"b6","series-title":"Neuroscience","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0306-4522(86)90002-3","article-title":"Cholinergic function and intellectual decline in Alzheimer's disease.","volume":"19","author":"Collerton","year":"1986"},{"key":"b7","series-title":"Exp Brain Res","first-page":"545","article-title":"Behavioral deficits after intrahippocampal fetal septal grafts in rats with selective fimbria-fornix lesions.","volume":"69","author":"Dalrymple-Alford","year":"1988"},{"key":"b8","series-title":"N Engl J Med","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1056\/NEJM198611133152008","article-title":"Cholinergic drugs in Alzheimer's disease.","volume":"315","author":"Davis","year":"1986"},{"key":"b9","series-title":"Prog Neuropsychopharmacol Biol Psychiatry","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/0278-5846(86)90012-6","article-title":"On the pathogenesis and therapy of dementia of the Alzheimer type: some neuropathological, biochemical, genetic and pharmacotherapeutic considerations.","volume":"10","author":"De Estable-Puig","year":"1986"},{"key":"b10","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0006-8993(85)90154-4","article-title":"Profound disturbances of spontaneous and learned behaviors following lesions of the nucleus basalis magnocellularis in the rat.","volume":"338","author":"Dubois","year":"1985"},{"key":"b11","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/0006-8993(82)90751-X","article-title":"Septal transplants restore maze learning in rats with fornix-fimbria lesions.","volume":"251","author":"Dunnett","year":"1982"},{"key":"b12","series-title":"Neuroscience","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1016\/0306-4522(86)90142-9","article-title":"Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease.","volume":"19","author":"Etienne","year":"1986"},{"key":"b13","series-title":"Adv Behav Biol","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1007\/978-1-4684-8643-8_67","article-title":"Anatomical organization of some cholinergic systems in the mammalian forebrain.","volume":"25","author":"Fibiger","year":"1981"},{"key":"b14","series-title":"Pharmacol Biochem Behav","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/S0091-3057(83)80023-9","article-title":"Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the neocortex in the rat.","volume":"18","author":"Flicker","year":"1983"},{"key":"b15","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1227\/00006123-198410000-00007","article-title":"Preliminary report: intracranial cholinergic drug infusion in patients with Alzheimer's disease.","volume":"15","author":"Harbaugh","year":"1984"},{"key":"b16","series-title":"Neurosci Lett","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/0304-3940(87)90016-4","article-title":"A disorder of cortical GABAergic innervation in Alzheimer's disease.","volume":"73","author":"Hardy","year":"1987"},{"key":"b17","series-title":"Can J Neurol Sci","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1017\/S0317167100036957","article-title":"Animal models of Alzheimer's disease: behavior, pharmacology, transplants.","volume":"13","author":"Haroutunian","year":"1986"},{"key":"b18","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/0006-8993(85)91088-1","article-title":"Memory impairments following basal forebrain lesions.","volume":"346","author":"Hepler","year":"1985"},{"key":"b19","series-title":"Prog Neuropsychopharmacol Biol Psychiatry","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/0278-5846(86)90017-5","article-title":"Drug therapy of Alzheimer's disease: realistic or not?","volume":"10","author":"Hollister","year":"1986"},{"key":"b20","series-title":"J Neurosci","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1523\/JNEUROSCI.06-01-00281.1986","article-title":"Organization of choline acetyl-transferase-containing structures in the forebrain of the rat.","volume":"6","author":"Ichikawa","year":"1986"},{"key":"b21","series-title":"Neurobiol Aging","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/0197-4580(86)90009-6","article-title":"Medial septal and nucleus basalis magnocellularis lesions produce order memory deficits in rats which mimic symptomatology of Alzheimer's disease.","volume":"7","author":"Kesner","year":"1986"},{"key":"b22","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/0006-8993(87)90783-9","article-title":"Fiber pathways of basal forebrain cholinergic neurons in monkeys.","volume":"406","author":"Kitt","year":"1987"},{"key":"b23","series-title":"Biomedical Polymers.","first-page":"113","article-title":"Controlled release of macromolecules from polymers","author":"Langer","year":"1980"},{"key":"b24","series-title":"J Biomed Mater Res","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1002\/jbm.820190806","article-title":"Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics.","volume":"19","author":"Leong","year":"1985"},{"key":"b25","series-title":"J Biomed Mater Res","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1002\/jbm.820200106","article-title":"Bioerodible polyanhydrides as drug-carrier matrices. II: Biocompatibility and chemical reactivity.","volume":"20","author":"Leong","year":"1986"},{"key":"b26","series-title":"Nature","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/300260a0","article-title":"Functional recovery following neural transplantation of embryonic septal nucleus in adult rats with septohippocampal lesions.","volume":"300","author":"Low","year":"1982"},{"key":"b27","series-title":"J Appl Polym Sci","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1002\/app.1988.070350316","article-title":"Polyanhydride microspheres as drug carriers. II. Microencapsulation by solvent removal.","volume":"35","author":"Mathiowitz","year":"1988"},{"key":"b28","series-title":"Surg Forum","first-page":"496","article-title":"Thrombus prevention without systemic anticoagulation using localized polymeric drug-delivery of heparin.","volume":"39","author":"Mayberg","year":"1988"},{"key":"b29","series-title":"J Comp Neurol","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1002\/cne.902140206","article-title":"Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey.","volume":"214","author":"Mesulam","year":"1983"},{"key":"b30","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/0006-8993(81)90478-9","article-title":"Controlled release of horseradish peroxidase from polymers: a method to improve histochemical localization and sensitivity.","volume":"212","author":"Moskowitz","year":"1981"},{"key":"b31","series-title":"Appl Neurophysiol","first-page":"65","article-title":"Moral perspectives in the use of embryonic cell transplantation for correction of nervous system disorders.","volume":"47","author":"Murphy","year":"1984"},{"key":"b32","series-title":"Q J Microsc Meth","first-page":"89","article-title":"Technical variation in Koeller's histochemical method for demonstrating cholinesterase activity.","volume":"104","author":"Naik","year":"1963"},{"key":"b33","series-title":"Prog Neuropsychopharmacol Biol Psychiatry","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/0278-5846(86)90022-9","article-title":"Pharmacotherapy in Alzheimer's disease: basis and rationale.","volume":"10","author":"Narang","year":"1986"},{"key":"b34","series-title":"J Exp Psychol (Anim Behav)","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1037\/0097-7403.2.2.97","article-title":"Remembrance of places passed: spatial memory in rats.","volume":"2","author":"Olton","year":"1976"},{"key":"b35","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/0006-8993(87)91408-9","article-title":"Monoami-nergic innervation of the frontal and temporal lobes in Alzheimer's disease.","volume":"401","author":"Palmer","year":"1987"},{"key":"b36","series-title":"Neurology","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1212\/WNL.38.2.219","article-title":"Intraventricular bethanechol infusion for Alzheimer's disease: results of double-blind and escalating-dose trials.","volume":"38","author":"Penn","year":"1988"},{"key":"b37","series-title":"Lancet","first-page":"189","article-title":"Necropsy evidence of central cholinergic deficits in senile dementia.","volume":"1","author":"Perry","year":"1977"},{"key":"b38","series-title":"Alzheimer's Disease.","first-page":"xvii","article-title":"Preface","author":"Reisberg","year":"1983"},{"key":"b39","series-title":"Neuroscience","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/0306-4522(84)90083-6","article-title":"Cortical projections arising from the basal forebrain: a study of cholinergic and noncholinergic components employing combined retrograde tracing and immunohistochemical localization of choline acetyltransferase.","volume":"13","author":"Rye","year":"1984"},{"key":"b40","series-title":"Brain Res","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0006-8993(86)91429-0","article-title":"Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections.","volume":"380","author":"Spencer","year":"1986"},{"key":"b41","series-title":"Ann Neurol","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/ana.410220305","article-title":"Effects of oral physostigmine in Alzheimer's disease.","volume":"22","author":"Stern","year":"1987"},{"key":"b42","series-title":"N Engl J Med","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1056\/NEJM198611133152001","article-title":"Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.","volume":"315","author":"Summers","year":"1986"},{"key":"b43","series-title":"J Neurosci","doi-asserted-by":"publisher","first-page":"3334","DOI":"10.1523\/JNEUROSCI.07-10-03334.1987","article-title":"Immunohistochemical localization of neuronal nicotinic receptors in the rodent central nervous system.","volume":"7","author":"Swanson","year":"1987"},{"key":"b44","series-title":"Ann Neurol","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1002\/ana.410140502","article-title":"Senile dementia of the Alzheimer type.","volume":"14","author":"Terry","year":"1983"},{"key":"b45","series-title":"Brain Res Rev","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/0165-0173(80)90011-9","article-title":"Cholinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats.","volume":"2","author":"Wenk","year":"1980"},{"key":"b46","series-title":"Neurology","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1212\/WNL.38.2.307","article-title":"Intraventricular bethanechol in Alzheimer's disease: a continuing controversy.","volume":"38","author":"Whitehouse","year":"1988"},{"key":"b47","series-title":"Science","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1126\/science.7058341","article-title":"Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.","volume":"215","author":"Whitehouse","year":"1982"},{"key":"b48","series-title":"Neuropsychobiology","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1159\/000118256","article-title":"Alzheimer's disease and serotonin: a review.","volume":"15","author":"Whitford","year":"1986"}],"container-title":["Journal of Neurosurgery"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/71\/1\/article-p105.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/71\/1\/article-p105.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/71\/1\/article-p105.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,26]],"date-time":"2023-03-26T21:18:30Z","timestamp":1679865510000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/71\/1\/article-p105.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1989,7]]},"references-count":48,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3171\/jns.1989.71.1.0105","relation":{},"ISSN":["0022-3085"],"issn-type":[{"value":"0022-3085","type":"print"}],"subject":[],"published":{"date-parts":[[1989,7]]}}}