Review
Longo FM and Massa SM. Small molecule modulation of neurotrophin receptors for the treatment of neurological disease. Nature Reviews Drug Discovery 2013 [This article was invited by Nature Reviews reflecting the pioneering role of Drs. Longo and Massa in the field of neurotrophin receptor therapeutics. Cover and featured article].
Discovery of p75 modulator ligands
Massa SM, Xie Y, Yang T, Harrington AW, Kim ML, Yoon SO, Kraemer R, Moore LA, Hempstead BL and Longo FM. Small, non-peptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J Neurosci 2006
Publications demonstrating activity of p75 modulator ligand LM11A-31 in preclinical models
Alzheimer's disease
Yang T, Knowles JK, Lu Q, Zhang H, Arancio 0, Moore LA, Chang T, Wang Q, Andreasson K, Rajadas J, Fuller GG, Xie Y, Massa SM, Longo FM. Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS ONE 2008
Knowles JK, Simmons DA, Nguyen T, Vander Griend L, Xie Y, Zhang H, Yang T, Pollak J, Chang T, Arancio O, Buckwalter M, Wyss-Coray T, Massa SM, Longo FM. A small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol Aging 2013
Nguyen TV. Shen L, Vander Griend L, Quach LN, Belichenko Np, Saw N, Yang T, Shamloo M, Wyss-Coray T, Massa SM, Longo FM. Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in APP-Lon-Swe transgenic mice. J Alz Dis 2014
Simmons DA, Knowles JK, Belichenko Np, Banerjee G, Finkle C, Massa SM, Longo FM. A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PLoS One 2014
James ML, Belichenko NP, Shuhendler AJ, Hoehne A, Andrews LE, Condon C, Nguyen TV, Reiser V, Jones P, Trigg W, Rao J, Gambhir SS, Longo FM. [18F]GE-180 PET detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer's disease. Theranostics 2017
Yang T, Tran KC, Zeng AY, Massa SM, Longo FM. Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies. Sci Rep. 2020 Nov 23;10(1):20322. doi: 10.1038/s41598-020-77210-y. PMID: 33230162; PMCID: PMC7683564.
Yang T, Liu H, Tran KC, Leng A, Massa SM, Longo FM. Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice. Acta Neuropathol Commun. 2020 Sep 5;8(1):156. doi: 10.1186/s40478-020-01034-0. PMID: 32891185; PMCID: PMC7487850.
Huntington's disease
Simmons DA, Belichenko NP, Ford EC, Semaan S, Monbureau M, Aiyaswamy S, Holman CM, Condon C, Shamloo M, Massa SM, Longo FM. A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice. Hum Mol Genet 2016
Simmons DA, James ML, Belichenko NP, Semaan S, Condon C, Kuan J, Shuhendler AJ, Miao Z, Chin FT, Longo FM. TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31. Hum Mol Genet 2018
Simmons DA, Mills BD, Butler Iii RR, Kuan J, McHugh TLM, Akers C, Zhou J, Syriani W, Grouban M, Zeineh M, Longo FM. Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31. Neurotherapeutics. 2021 Apr;18(2):1039-1063. doi: 10.1007/s13311-021-01023-8. Epub 2021 Mar 30. PMID: 33786806; PMCID: PMC8423954.
HIV dementia
Meeker RB, Poulton W, Feng WH, Hudson L, Longo FM. Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model. J Neuroimmune Pharmacol 2012
Meeker RB, Poulton W, Clary G, Schriver M, Longo FM. Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. Exp Neurol 2016
Killebrew DA, Williams KS, Xie Y, Longo F, Meeker RB. Suppression of HIV- associated Macrophage Activation by a p75 Neurotrophin Receptor Ligand. J Neuroimmune Pharmacol. 2021 Jul 22. doi: 10.1007/s11481-021-10002-x. Epub ahead of print. PMID: 34296391.
Fogle JE, Hudson L, Thomson A, Sherman B, Gruen M, Lacelles BD, Colby BM, Clary G, Longo F, Meeker RB. Improved neurocognitive performance in FIV infected cats following treatment with the p75 neurotrophin receptor ligand LM11A-31. J Neurovirol. 2021 Apr;27(2):302-324. doi: 10.1007/s13365-021-00956-2. Epub 2021 Mar 4. PMID: 33661457.
Other disorders
Pehar M, Cassina P, Vargas MR, Xie Y, Beckman JS, Massa SM, Longo FM, Barbeito L. Modulation of p75-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain. Eur J Neurosci 2006
James SE, Burden H, Burgess R, Xie Y, Yang T, Massa SM, Longo FM, Lu Q. Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology 2008
Tep C, Lim TH, Ko PO, Getahun 5, Ryu JC, Goettl VM, Massa SM, Basso M, Longo FM, and Yoon SO. Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J Neurosci 2013
Shi J, Longo FM and Massa SM. A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury. Stem Cells 2013
Friesland A, Weng Z, Duenas M, Massa SM, Longo FM, Lu Q. Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. Neurotoxicology 2014
Darcq E, Morisot N, Phamluong K, Warnault V, Jeanblanc J, Longo FM, Massa SM, Ron D. The neurotrophic factor receptor p75 in the rat dorsolateral striatum drives excessive alcohol drinking. J Neurosci 2016
Haefeli J, Ferguson AR, Bingham D, Orr A, Won SJ, Lam TI, Shi J, Hawley S, Liu J, Swanson RA, Massa SM. A data-driven approach for evaluating multi-modal therapy in traumatic brain injury. Sci Rep 2017
Minnone G, Soligo M, Caiello I, Prencipe G, Manni L, Marafon DP, Magni-Manzoni S, Manzo A, De Benedetti F, Bracci-Laudiero L. ProNGF-p75NTR axis plays a proinflammatory role in inflamed joints: a novel pathogenic mechanism in chronic arthritis. RMD Open 2017
Ryu JC, Tooke K, Malley SE, Soulas A, Weiss T, Ganesh N, Saidi N, Daugherty S, Saragovi U, Ikeda Y, Zabbarova I, Kanai AJ, Yoshiyama M, Farhadi HF, de Groat WC, Vizzard MA, Yoon SO. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 2018
Zabbarova IV, Ikeda Y, Carder EJ, Wipf P, Wolf-Johnston AS, Birder LA, Yoshimura N, Getchell SE, Almansoori K, Tyagi P, Fry CH, Drake MJ, Kanai AJ. Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourol Urodyn 2018
Ji M, Yuan H, Yuan S, Xia J, Yang J. The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments. Behav Brain Res 2018.
Elshaer SL, Alwhaibi A, Mohamed R, Lemtalsi T, Coucha M, Longo FM, El-Remessy AB. Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway. Diabetologia 2019
Xie Y, Meeker RB, Massa SM, Longo FM. Modulation of the p75 neurotrophin receptor suppresses age-related basal forebrain cholinergic neuron degeneration. Sci Rep 2019
Zhang D, Zhao S, Zhang Z, Xu D, Lian D, Wu J, He D, Sun K, Li L. Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis. J Neuroinflammation. 2021 Nov 2;18(1):253. doi: 10.1186/s12974-021-02294-w. PMID: 34727939; PMCID: PMC8561879.
Aby K, Antony R, Eichholz M, Srinivasan R, Li Y. Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle. Life Sci. 2021 Dec 1;286:120067. doi: 10.1016/j.lfs.2021.120067. Epub 2021 Oct 19. PMID: 34678261; PMCID: PMC8595791.
Qin X, Wang J, Chen S, Liu G, Wu C, Lv Q, He X, Bai X, Huang W, Liao H. Astrocytic p75NTR expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption. Glia. 2022 Jan 22. doi: 10.1002/glia.24146. PMID: 35064700.
Nguyen TV, Crumpacker RH, Calderon KE, Garcia FG, Zbesko JC, Frye JB, Gonzalez S, Becktel DA, Yang T, Tavera-Garcia MA, Morrison HW, Schnellmann RG, Longo FM, Doyle KP. Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery. J Pharmacol Exp Ther. 2022 Feb;380(2):126-141. doi: 10.1124/jpet.121.000711.
Trk Receptors
Publications demonstrating activity of TrkB receptor modulator LM22A-4 in preclinical models
Massa SM, YangT XieY, ShiJ, BilgenM, Joyce IN, NehamaD, Rajadas J and Longo FM. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest 2010
Schmid DA, Yang T, Ogier M, Adams I, Mirakhur Y, Wang Q, Massa SM, Longo FM, Katz DM. A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci 2012
Han J, Pollak J, Yang T, Siddiqui MR, Doyle KP, Taravosh-Lahn K, Cekanaviciute E, Han A, Goodman JZ, Jones B, Jing D, Massa SM, Longo FM, Buckwalter MS. Delayed administration of a small molecule TrkB ligand promotes recovery after hypoxic-ischemic stroke. Stroke 2012
Simmons DA, Belichenko Np, Yang T, Condon C, Monbureau M, Shamloo M, Jing D, Massa SM, and LONGO FM. A small molecule TrkB ligand reduces motor impairment and neuropathology in R6-2 and BACHD mouse models of Huntington's Disease. J Neurosci 2013
Al-Qudah M, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JR. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 2014
Kajiya M, Takeshita K, Kittaka M, Matsuda S, Ouhara K, Takeda K, Takata T, Kitagawa M, Fujita T, Shiba H, Kurihara H. BDNF mimetic compound LM22A-4 regulates cementoblast differentiation via the TrkB-ERK/Akt signaling cascade.
Int Immunopharmacol 2014
Kron M, Lang M, Adams I, Sceniak M, LONGO FM, and Katz DM. A BDNF loop domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome. Dis Model Mech 2014
Yu G and Wang W. Protective effects of LM22A-4 on injured spinal cord nerves. Int J Clin Exp Path 2015.
Warnault V, Darcq E, Morisot N, Phamluong K, Wilbrecht L, Massa SM, Longo FM, Ron D. The BDNF valine 68 to methionine polymorphism increases compulsive alcohol drinking in mice that is reversed by tropomyosin receptor kinase B activation. Biol Psychiatry 2016
Yang T, Massa SM, Tran KC, Simmons DA, Rajadas J, Zeng AY, Jang T, Carsanaro S, Longo FM. A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth. Neuropharm 2016
Li W, Bellot-Saez A, Phillips ML, Yang T, Longo FM, Pozzo-Miller L. A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice. Dis Model Mech 2017
Nomura T, Musial TF, Marshall JJ, Zhu Y, Remmers CL, Xu J, Nicholson DA, Contractor A. Delayed maturation of fast-spiking interneurons is rectified by activation of the TrkB receptor in the mouse model of fragile X syndrome. J Neurosci 2017
Gu F, Parada I, Yang T, Longo FM, Prince DA. Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons. Neurobiol Dis 2018
Ali Shariati M, Kumar V, Yang T, Chakraborty C, Barres BA, Longo FM, Liao YJ. A small molecule TrkB neurotrophin receptor partial agonist as possible treatment for experimental nonarteritic anterior ischemic optic neuropathy. Curr Eye Res 2018
Totoson P, Pedard M, Marie C, Demougeot C. Activation of endothelial TrkB receptors induces relaxation of resistance arteries. Vascul Pharmacol 2018
Pedard M, Quirie A, Totoson P, Verhoeven F, Garnier P, Tessier A, Demongeot C, Marie C. Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis. Atherosclerosis 2018.
Geraghty AC, Gibson EM, Ghanem RA, Greene JJ, Ocampo A, Goldstein AK, Ni L, Yang T, Marton RM, Pa?ca SP, Greenberg ME, Longo FM, Monje M. Loss of adaptive myelination contributes to methotrexate chemotherapy-related cognitive impairment. Neuron 2019
Nguyen HTH, Wood RJ, Prawdiuk AR, Furness SGB, Xiao J, Murray SS, Fletcher JL. TrkB Agonist LM22A-4 increases oligodendroglial populations during myelin repair in the corpus callosum. Front Mol Neurosci 2019
Gu F, Parada I, Yang T, Longo FM, Prince DA. Partial activation of TrkB receptors corrects interneuronal calcium channel dysfunction and reduces epileptogenic activity in neocortex following injury. Cereb Cortex 2020
Kipnis PA, Sullivan BJ, Carter BM and Kadam SD. TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice. JCI Insight 2020
Fletcher JL, Dill LK, Wood RJ, Wang S, Robertson K, Murray SS, Zamani A and Semple BD. Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury. Exp Neurol 2021
De Deus JL, Amorim MR, Ribeiro AB, Barcellos-Filho PCG, Ceballos CC, Branco LGS, Cunha AOS, Leao RM. Loss of brain-derived neurotrophic factor mediates inhibition of hippocampal long-term potentiation by high-intensity sound. Cell Mol Neurobiol 2021
Gu F, Parada I, Yang T, Longo FM and Prince DA. Chronic partial TrkB activation reduces seizure and mortality in a mouse model of Dravet syndrome. Proc Nat Acad Sci 2022
