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Benzodiazepines in Alzheimer’s disease: beneficial or detrimental effects

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Abstract

Dementia is considered a clinical syndrome characterized by cognitive dysfunction and memory loss. Alzheimer's disease (AD) is the most common type of dementia. AD is linked with the turbulence of diverse neurotransmitters including gamma-aminobutyric acid (GABA). Notably, GABA in the brain and cerebrospinal fluid was reduced in AD. Thus, allosteric modulation of the GABA effect by benzodiazepines (BDZs) may improve the clinical outcomes of AD patients. Therefore, the objective of the present review was to reveal the possible role of BDZs on the pathogenesis and clinical outcomes in AD patients. Though BDZs may adversely affect cognitive functions mainly in elderly patients, herein it was postulated that BDZs may have beneficial, neutral, or detrimental effects in AD. Taken together, there is strong controversy regarding the use of BDZs and the risk for the development of AD. Therefore, experimental, preclinical and clinical studies are critical to determine the potential protective or detrimental effects of BDZs on AD neuropathology.

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References

  • Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, Duong A, Suhy J, Oh J, Lau WC (2011) Tramiprosate in mild-to-moderate Alzheimer’s disease–a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase study). Arch Med Sci 7:102–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aldaz P, Garjón J, Beitia G, Beltrán I, Librero J, Ibáñez B, Arroyo P, Ariz MJ (2021) Association between benzodiazepine use and development of dementia. Medicina Clínica (english Edition) 156:107–111

    Article  CAS  Google Scholar 

  • Almohaish S, Sandler M, Brophy GM (2021) Time is brain: acute control of repetitive seizures and status epilepticus using alternative routes of administration of benzodiazepines. J Clin Med 10:1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alsubaie N, Al-kuraishy HM, Al-Gareeb AI, Alharbi B, De Waard M, Sabatier J-M, Saad HM, Batiha GE-S (2022) Statins use in Alzheimer disease: bane or boon from frantic search and narrative review. Brain Sci 12:1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aranđelović J, Santrač A, Batinić B, Todorović L, Stevanović V, Tiruveedhula VVNPB, Sharmin D, Rashid F, Stanojević B, Cook JM (2022) Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer’s disease. CNS Neurosci Ther 28(11):1767–1778

    Article  PubMed  PubMed Central  Google Scholar 

  • Arshad S, Butt J, Iqbal J, ul Hassan SS, (2018) Abuses and misuses of benzodiazepines and antidepressents; a review. Mod Appl Pharm Pharmacol 1:1–6

    Google Scholar 

  • Baek Y-H, Lee H, Kim WJ, Chung J-E, Pratt N, Ellett LK, Shin J-Y (2020) Uncertain association between benzodiazepine use and the risk of dementia: a cohort study. J Am Med Dir Assoc 21(201–211):e202

    Google Scholar 

  • Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol 19:437–454

    Article  PubMed  Google Scholar 

  • Bellantuono C, Martellini M, Orsolini L (2019) Benzodiazepines and Z-Drugs in Pregnancy. Perinatal Psychopharmacology, Springer, Cham

    Book  Google Scholar 

  • Bounds CG, Nelson VL (2020) Benzodiazepines. StatPearls [Internet]. StatPearls Publishing, United States

    Google Scholar 

  • Brady ML, Pilli J, Lorenz-Guertin JM, Das S, Moon CE, Graff N, Jacob TC (2018) Depolarizing, inhibitory GABA type a receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling. Neuropharmacology 128:324–339

    Article  CAS  PubMed  Google Scholar 

  • Brigo F, Lattanzi S (2020) Anticonvulsant agents: benzodiazepines (clobazam, clonazepam, diazepam, lorazepam, midazolam). NeuroPsychopharmacotherapy 2020:1–8

    Google Scholar 

  • Caruso A, Nicoletti F, Mango D, Saidi A, Orlando R, Scaccianoce S (2018) Stress as risk factor for Alzheimer’s disease. Pharmacol Res 132:130–134

    Article  PubMed  Google Scholar 

  • Charalambous M, Volk HA, Van Ham L, Bhatti SF (2021) First-line management of canine status epilepticus at home and in hospital-opportunities and limitations of the various administration routes of benzodiazepines. BMC Vet Res 17:1–19

    Article  Google Scholar 

  • Chen X-Q, Mobley WC (2019) Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front Neurosci 13:659

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Strickland MR, Soranno A, Holtzman DM (2021) Apolipoprotein E: structural insights and links to Alzheimer disease pathogenesis. Neuron 109:205–221

    Article  CAS  PubMed  Google Scholar 

  • Cho S, Park JS, Kang Y-K (2011) Dual functions of histone-lysine N-methyltransferase Setdb1 protein at promyelocytic leukemia-nuclear body (PML-NB): maintaining PML-NB structure and regulating the expression of its associated genes. J Biol Chem 286:41115–41124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornett EM, Novitch MB, Brunk AJ, Davidson KS, Menard BL, Urman RD, Kaye AD (2018) New benzodiazepines for sedation. Best Pract Res Clin Anaesthesiol 32:149–164

    Article  PubMed  Google Scholar 

  • Dailly E, Bourin M (2008) The use of benzodiazepines in the aged patient: clinical and pharmacological considerations. Pak J Pharm Sci 21:144–150

    CAS  PubMed  Google Scholar 

  • De Gage SB, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B (2014) Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 349:g5205

    Article  Google Scholar 

  • Defrancesco M, Marksteiner J, Fleischhacker WW, Blasko I (2015) Use of benzodiazepines in Alzheimer’s disease: a systematic review of literature. Int J Neuropsychopharmacol 18:pyv055

    Article  PubMed  PubMed Central  Google Scholar 

  • Delgado-Roche L, Santes-Palacios R, Herrera JA, Hernández SL, Riera M, Fernández MD, Mesta F, Garrido G, Rodeiro I, Espinosa-Aguirre JJ (2020) Interaction of Thalassia testudinum metabolites with cytochrome P450 enzymes and its effects on benzo (a) pyrene-induced mutagenicity. Mar Drugs 18:566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Della Torre C, Maggioni D, Ghilardi A, Parolini M, Santo N, Landi C, Madaschi L, Magni S, Tasselli S, Ascagni M (2018) The interactions of fullerene C60 and Benzo (α) pyrene influence their bioavailability and toxicity to zebrafish embryos. Environ Pollut 241:999–1008

    Article  CAS  PubMed  Google Scholar 

  • Desmidt T, Delrieu J, Lebouvier T, Robert G, David R, Balageas A-C, Surget A, Belzung C, Arlicot N, Ribeiro M-J (2019) Benzodiazepine use and brain amyloid load in nondemented older individuals: a florbetapir PET study in the multidomain Alzheimer preventive trial cohort. Neurobiol Aging 84:61–69

    Article  CAS  PubMed  Google Scholar 

  • Diehl T, Mullins R, Kapogiannis D (2017) Insulin resistance in Alzheimer’s disease. Transl Res 183:26–40

    Article  CAS  PubMed  Google Scholar 

  • Duka T, Ott H, Rohloff A, Voet B (1996) The effects of a benzodiazepine receptor antagonist β-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills. Psychopharmacology 123:361–373

    Article  CAS  PubMed  Google Scholar 

  • Dyer AH, Murphy C, Lawlor B, Kennelly SP, Segurado R, Kennelly S, Rikkert MGO, Howard R, Pasquier F, Börjesson-Hanson A (2020) Cognitive outcomes of long-term benzodiazepine and related drug (BDZR) use in people living with mild to moderate Alzheimer’s disease: results from NILVAD. J Am Med Dir Assoc 21:194–200

    Article  PubMed  Google Scholar 

  • Edinoff AN, Nix CA, Hollier J, Sagrera CE, Delacroix BM, Abubakar T, Cornett EM, Kaye AM, Kaye AD (2021) Benzodiazepines: uses, dangers, and clinical considerations. Neurol Int 13:594–607

    Article  PubMed  PubMed Central  Google Scholar 

  • Edinoff AN, Nix CA, Odisho AS, Babin CP, Derouen AG, Lutfallah SC, Cornett EM, Murnane KS, Kaye AM, Kaye AD (2022) Novel designer benzodiazepines: comprehensive review of evolving clinical and adverse effects. Neurol Int 14:648–663

    Article  PubMed  PubMed Central  Google Scholar 

  • Etherington L-A, Mihalik B, Pálvölgyi A, Ling I, Pallagi K, Kertész S, Varga P, Gunn BG, Brown AR, Livesey MR (2017) Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent. Neuropharmacology 125:353–364

    Article  CAS  PubMed  Google Scholar 

  • Ettcheto M, Olloquequi J, Sánchez-López E, Busquets O, Cano A, Manzine PR, Beas-Zarate C, Castro-Torres RD, García ML, Bulló M (2020) Benzodiazepines and related drugs as a risk factor in Alzheimer’s disease dementia. Front Aging Neurosci 11:344

    Article  PubMed  PubMed Central  Google Scholar 

  • Fastbom J, Forsell Y, Winblad B (1998) Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis Assoc Disord 12:14–17

    Article  CAS  PubMed  Google Scholar 

  • Frias AT, Fernandes GG, Zangrossi H Jr (2019) GABAA/benzodiazepine receptors in the dorsal periaqueductal gray mediate the panicolytic but not the anxiolytic effect of alprazolam in rats. Behav Brain Res 364:99–105

    Article  CAS  PubMed  Google Scholar 

  • Frost D, Meechoovet B, Wang T, Gately S, Giorgetti M, Shcherbakova I, Dunckley T (2011) β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS ONE 6:e19264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallacher J, Elwood P, Pickering J, Bayer A, Fish M, Ben-Shlomo Y (2012) Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS). J Epidemiol Comm Health 66:869–873

    Article  Google Scholar 

  • Gallet Q, Bouteloup V, Locatelli M, Habert M-O, Chupin M, Delrieu J, Lebouvier T, Robert G, David R, Bulteau S (2022) Benzodiazepine use and neuroimaging markers of Alzheimer’s disease in nondemented older individuals: an MRI and 18F Florbetapir PET study in the MEMENTO cohort. Neuropsychopharmacology 47:1114–1120

    Article  CAS  PubMed  Google Scholar 

  • Gomiero A, Strafella P, Pellini G, Salvalaggio V, Fabi G (2018) Comparative effects of ingested PVC micro particles with and without adsorbed benzo (a) pyrene vs spiked sediments on the cellular and sub cellular processes of the benthic organism Hediste diversicolor. Frontiers in Mar Sci 5:99

    Article  Google Scholar 

  • Gonzalez J, Upadhyaya VD, Manna ZT, Sharma AR, Christopher J, Douedi S, Sen S (2022) Paradoxical excitation following intravenous lorazepam administration for alcohol withdrawal–a case presentation and literature review. J Pharm Pract. https://doi.org/10.1177/08971900221097182

    Article  PubMed  PubMed Central  Google Scholar 

  • Guerrini G, Ciciani G, Cambi G, Bruni F, Selleri S, Guarino C, Melani F, Montali M, Martini C, Ghelardini C (2009) Synthesis, in vivo evaluation, and molecular modeling studies of new pyrazolo [5, 1-c][1, 2, 4] benzotriazine 5-oxide derivatives. Identification of a bifunctional hydrogen bond area related to the inverse agonism. J Med Chem 52:4668–4682

    Article  CAS  PubMed  Google Scholar 

  • Harris D, Clayton T, Cook J, Sahbaie P, Halliwell RF, Furtmüller R, Huck S, Sieghart W, DeLorey TM (2008) Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the α5 subunit. J Med Chem 51:3788–3803

    Article  CAS  PubMed  Google Scholar 

  • Henstridge CM, Hyman BT, Spires-Jones TL (2019) Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat Rev Neurosci 20:94–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Islam MM, Iqbal U, Walther B, Atique S, Dubey NK, Nguyen P-A, Poly TN, Masud JHB, Li Y-CJ, Shabbir S-A (2016) Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology 47:181–191

    Article  PubMed  Google Scholar 

  • Izza MA, Lunt E, Gordon AL, Gladman JR, Armstrong S, Logan P (2020) Polypharmacy, benzodiazepines, and antidepressants, but not antipsychotics, are associated with increased falls risk in UK care home residents: a prospective multi-centre study. Eur Geriatr Med 11:1043–1050

    Article  PubMed  PubMed Central  Google Scholar 

  • Ji B, Liu S, Xue Y, He X, Man VH, Xie X-Q, Wang J (2019) Prediction of drug–drug interactions between opioids and overdosed benzodiazepines using physiologically based pharmacokinetic (PBPK) modeling and simulation. Drugs R&d 19:297–305

    Article  CAS  Google Scholar 

  • Joyce G, Ferido P, Thunell J, Tysinger B, Zissimopoulos J (2022) Benzodiazepine use and the risk of dementia. Alzheimer’s Dementia 8:e12309

    PubMed  PubMed Central  Google Scholar 

  • Keskin E, Can EY, Aydın HA, Işık E, Özgen U, Şimşek K, Cengil O, Başar C, Kalaycı M (2021) The preventative effect of of Ro5-4864 (peripheral benzodiazepine receptor agonist) on spinal epidural fibrosis after laminectomy in a rat model. Neurol Res 43:1107–1115

    Article  CAS  PubMed  Google Scholar 

  • Kleinberger G, Wils H, Ponsaerts P, Joris G, Timmermans JP, Van Broeckhoven C, Kumar-Singh S (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735–747

    Article  CAS  PubMed  Google Scholar 

  • Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT (2021) Tendinopathy. Nat Rev Dis Primers 7:1–21

    Article  Google Scholar 

  • Kramer PF, Twedell EL, Shin JH, Zhang R, Khaliq ZM (2020) Axonal mechanisms mediating γ-aminobutyric acid receptor type a (GABA-A) inhibition of striatal dopamine release. Elife. https://doi.org/10.7554/eLife.55729

    Article  PubMed  PubMed Central  Google Scholar 

  • Kurlawala Z, Roberts JA, McMillan JD, Friedland RP (2018) Diazepam toxicity presenting as a dementia disorder. J Alzheimers Dis 66:935–938

    Article  PubMed  Google Scholar 

  • Kwakowsky A, Calvo-Flores Guzmán B, Pandya M, Turner C, Waldvogel HJ, Faull RL (2018a) GABAA receptor subunit expression changes in the human Alzheimer’s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. J Neurochem 145:374–392

    Article  CAS  PubMed  Google Scholar 

  • Kwakowsky A, Guzmán BC-F, Govindpani K, Waldvogel HJ, Faull RL (2018b) Gamma-aminobutyric acid a receptors in Alzheimer’s disease: highly localized remodeling of a complex and diverse signaling pathway. Neural Regen Res 13:1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwakowsky A, Waldvogel HJ, Faull RL (2021) Therapeutic potential of alpha 5 subunit containing GABAA receptors in Alzheimer’s disease. Neural Regen Res 16:1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamvu G, Soliman AM, Manthena SR, Gordon K, Knight J, Taylor HS (2019) Patterns of prescription opioid use in women with endometriosis: evaluating prolonged use, daily dose, and concomitant use with benzodiazepines. Obstet Gynecol 133:1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee BY, Ban JY, Seong YH (2005) Chronic stimulation of GABAA receptor with muscimol reduces amyloid β protein (25–35)-induced neurotoxicity in cultured rat cortical cells. Neurosci Res 52:347–356

    Article  CAS  PubMed  Google Scholar 

  • LeQuang JA (2021) The effects of benzodiazepines on memory. Naturally occurring benzodiazepines, endozepines, and their receptors. CRC Press, Boca Raton

    Google Scholar 

  • Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, Halabisky B, Deng C, Mahley RW, Huang Y (2009) GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5:634–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Ma J, Jin Y, Li N, Zheng R, Mu W, Wang J, Si JH, Chen J, Shang HC (2020) Benzodiazepines for treatment of patients with delirium excluding those who are cared for in an intensive care unit. The Cochrane Database Sys Rev 2:Cd012670

    Google Scholar 

  • Lin YH, Chen MH, Chang YC, Chen L, Hsiung CA, Wu SI (2022) Prevalence of exposure to benzodiazepines among pregnant women in Taiwan: a nationwide longitudinal study. J Sleep Res. https://doi.org/10.1111/jsr.13678

    Article  PubMed  PubMed Central  Google Scholar 

  • Lombardi N, Bettiol A, Crescioli G, Ravaldi C, Bonaiuti R, Venegoni M, Vighi GD, Mugelli A, Mannaioni G, Vannacci A (2020) Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments. Intern Emerg Med 15:1291–1302

    Article  PubMed  Google Scholar 

  • Manchester KR, Maskell PD, Waters L (2018) Experimental versus theoretical log D7. 4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances. Drug Test Anal 10:1258–1269

    Article  CAS  Google Scholar 

  • Marsh J, Alifragis P (2018) Synaptic dysfunction in Alzheimer’s disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention. Neural Regen Res 13:616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mohamad FH, Has ATC (2019) The α5-containing GABAA receptors—a brief summary. J Mol Neurosci 67:343–351

    Article  CAS  PubMed  Google Scholar 

  • Moustafa RE, Tarbah F, Saeed HS, Sharif SI (2021) Designer benzodiazepines versus prescription benzodiazepines: can structural relation predict the next step? Crit Rev Toxicol 51:249–263

    Article  CAS  PubMed  Google Scholar 

  • Nafti M, Sirois C, Kröger E, Carmichael P-H, Laurin D (2020) Is benzodiazepine use associated with the risk of dementia and cognitive impairment–not dementia in older persons? The Canadian study of health and aging. Ann Pharmacother 54:219–225

    Article  PubMed  Google Scholar 

  • Noguchi Y, Ueno A, Katsuno H, Otsubo M, Yoshida A, Kanematsu Y, Sugita I, Tachi T, Tsuchiya T, Teramachi H (2018) Analyses of non-benzodiazepine-induced adverse events and prognosis in elderly patients based on the Japanese adverse drug event report database. J Pharmaceut Health Care Sci 4:10

    Article  Google Scholar 

  • Ochoa-de la Paz LD, Gulias-Cañizo R, Ruíz-Leyja ED, Sánchez-Castillo H, Parodí J (2021) The role of GABA neurotransmitter in the human central nervous system, physiology, and pathophysiology. Revista Mexicana De Neurociencia 22:67–76

    Article  Google Scholar 

  • Pomara N, Bruno D, Sidtis JJ, Lutz MW, Greenblatt DJ, Saunders AM, Roses AD (2011) Translocase of outer mitochondrial membrane 40 homolog (TOMM40) poly-T length modulates lorazepam-related cognitive toxicity in healthy APOE ε4-negative elderly. J Clin Psychopharmacol 31:544–546

    Article  PubMed  Google Scholar 

  • Qu J, Yan H, Zheng Y, Xue F, Zheng Y, Fang H, Chang Y, Yang H, Zhang J (2018) The molecular mechanism of alpha-synuclein dependent regulation of protein phosphatase 2A activity. Cell Physiol Biochem 47:2613–2625

    Article  CAS  PubMed  Google Scholar 

  • Ratner MH, Downing SS, Guo O, Odamah KE, Stewart TM, Kumaresan V, Robitsek RJ, Xia W, Farb DH (2021) Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer’s disease. Heliyon 7:e07895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson K, Loke Y, Savva GM, Howard RJ, Boyd P, Aldus C, Maidment ID, Steel N, Arthur A, Ballard C (2018) P4–387: UNINTENDED EFFECTS OF Z-DRUGS (ZOLPIDEM, ZOPICLONE AND ZALEPLON) IN PEOPLE LIVING WITH DEMENTIA. Alzheimers Dement 14:P1622–P1622

    Article  Google Scholar 

  • Rissman RA, De Blas AL, Armstrong DM (2007) GABAA receptors in aging and Alzheimer’s disease. J Neurochem 103:1285–1292

    Article  CAS  PubMed  Google Scholar 

  • Saarelainen L, Tolppanen AM, Koponen M, Tanskanen A, Tiihonen J, Hartikainen S, Taipale H (2018) Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: a matched cohort study. Int J Geriatr Psychiatry 33:583–590

    Article  PubMed  Google Scholar 

  • Salzman CE, Lebowitz BD (1991) Anxiety in the elderly: Treatment and research. The chapters were prepared and presented at a small workshop in Boston in Jan 1989. Springer Publishing Company, Cham

    Google Scholar 

  • Salzman C (2020) Do benzodiazepines cause Alzheimer’s disease? : Am psychiatric assoc. Am J Psyc. https://doi.org/10.1176/appi.ajp.2020.20040375

    Article  Google Scholar 

  • Savić MM, Majumder S, Huang S, Edwankar RV, Furtmüller R, Joksimović S, Clayton T Sr, Ramerstorfer J, Milinković MM, Roth BL (2010) Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at α1 plus α5 versus α2 plus α3 subunits account for dissimilarities in behavioral effects in rats? Prog Neuropsychopharmacol Biol Psychiatry 34:376–386

    Article  PubMed  PubMed Central  Google Scholar 

  • Schieveld JN, Strik JJ, Bruining H (2018) On benzodiazepines, paradoxical agitation, hyperactive delirium, and chloride homeostasis. Crit Care Med 46:1558–1559

    Article  PubMed  Google Scholar 

  • Sieghart W, Savić MM (2018) International Union of Basic and Clinical Pharmacology. CVI: GABA(A) Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans. Pharmacol Rev 70:836–878

    Article  CAS  PubMed  Google Scholar 

  • Smith AJ, Tett SE (2009) How do different age groups use benzodiazepines and antidepressants? Analysis of an Australian administrative database, 2003–6. Drugs Aging 26:113–122

    Article  CAS  PubMed  Google Scholar 

  • Sontag J-M, Sontag E (2014) Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci 7:16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stonnington CM, Snyder PJ, Hentz JG, Reiman EM, Caselli RJ (2009) Double-blind crossover study of the cognitive effects of lorazepam in healthy apolipoprotein E (APOE)-ε4 carriers. J Clin Psychiatry 70:4746

    Article  Google Scholar 

  • Tanimukai H, Grundke-Iqbal I, Iqbal K (2005) Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am J Pathol 166:1761–1771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M (2019) Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomed 14:5541

    Article  CAS  Google Scholar 

  • Trevisan K, Cristina-Pereira R, Silva-Amaral D, Aversi-Ferreira TA (2019) Theories of aging and the prevalence of Alzheimer’s disease. BioMed Res Int 2019:1–9

    Article  Google Scholar 

  • Vatanabe I, Manzine P, Cominetti M (2020) Historic concepts of dementia and Alzheimer’s disease: from ancient times to the present. Rev Neurol (paris) 176:140–147

    Article  CAS  PubMed  Google Scholar 

  • Vellas B, Sol O, Snyder JP, Ousset P-J, Haddad R, Maurin M, Lemarié J-C, Désiré L, Pando PM (2011) EHT0202 in Alzheimer’s disease: a 3 month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 8:203–212

    Article  CAS  PubMed  Google Scholar 

  • Vlad CS, Dumitrascu V, Vlad DC, Cimporescu A, Popescu R, Dehelean L, Marincu I, Citu IM, POENARU D, (2017) Fast and simple method for simultaneous detection and quantification of diazepam and desmethyldiazepam in plasma samples in psychiatric patients by GC-MS-FID. Rev Chim (bucharest) 68:530–533

    Article  CAS  Google Scholar 

  • Vöglein J, Ricard I, Noachtar S, Kukull WA, Dieterich M, Levin J, Danek A (2020) Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course. J Neurol 267:2941–2948

    Article  PubMed  PubMed Central  Google Scholar 

  • Wan H, Warburton E, Zhu X, Koder T, Park Y, Aggleton JP, Cho K, Bashir Z, Brown M (2004) Benzodiazepine impairment of perirhinal cortical plasticity and recognition memory. Eur J Neurosci 20:2214–2224

    Article  CAS  PubMed  Google Scholar 

  • Whittington RA, Virág L, Gratuze M, Lewkowitz-Shpuntoff H, Cheheltanan M, Petry F, Poitras I, Morin F, Planel E (2019) Administration of the benzodiazepine midazolam increases tau phosphorylation in the mouse brain. Neurobiol Aging 75:11–24

    Article  CAS  PubMed  Google Scholar 

  • Wick J (2013) The history of benzodiazepines. The Consul Pharm 28:538–548

    Article  Google Scholar 

  • Williams AM (2018) Coadministration of intramuscular olanzapine and benzodiazepines in agitated patients with mental illness. Mental Health Clin 8:208–213

    Article  Google Scholar 

  • Williams T, Borchelt DR, Chakrabarty P (2020) Therapeutic approaches targeting apolipoprotein E function in Alzheimer’s disease. Mol Neurodegener 15:1–19

    Article  Google Scholar 

  • Wingo AP, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM, Dammer EB, Robins C, Beach TG, Reiman EM (2021) Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis. Nat Genet 53:143–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Lavrencic L, Radford K, Booth A, Yoshimura S, Anstey KJ, Anderson CS, Peters R (2021) Systematic review of coexistent epileptic seizures and Alzheimer’s disease: Incidence and prevalence. J Am Geriatr Soc 69:2011–2020

    Article  PubMed  Google Scholar 

  • Yamazaki Y, Zhao N, Caulfield TR, Liu C-C, Bu G (2019) Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15:501–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshiike Y, Kimura T, Yamashita S, Furudate H, Mizoroki T, Murayama M, Takashima A (2008) GABAA receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3:e3029

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Shao H, Dong Y, Swain CA, Yu B, Xia W, Xie Z (2014) Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice. Transl Neurodegener 3:1–7

    Article  Google Scholar 

  • Zhao Y, Wang Z, Dai J, Chen L, Huang Y, Zhan Z (2012) Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice. Behav Brain Res 228:339–350

    Article  CAS  PubMed  Google Scholar 

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  1. Professor in Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq

    Hayder M. Al-kuraishy & Ali I. Al-Gareeb

  2. Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744, Egypt

    Hebatallah M. Saad

  3. Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt

    Gaber El-Saber Batiha

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  1. Hayder M. Al-kuraishy
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  2. Ali I. Al-Gareeb
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  3. Hebatallah M. Saad
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  4. Gaber El-Saber Batiha
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Contributions

HMA-K and AIA conceptualized the manuscript, wrote, edited and reviewed the main text and approved the final edition of the manuscript. HMS and GE-SB prepared the figures, wrote, corrected, amended and approved the final edition of the manuscript.

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Correspondence to Hebatallah M. Saad or Gaber El-Saber Batiha.

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Al-kuraishy, H.M., Al-Gareeb, A.I., Saad, H.M. et al. Benzodiazepines in Alzheimer’s disease: beneficial or detrimental effects. Inflammopharmacol 31, 221–230 (2023). https://doi.org/10.1007/s10787-022-01099-4

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