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 

 

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


HIV dementia


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


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


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 


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, Paşca 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