BNN27 is a blood-brain barrier-penetrant, selective NGF receptor ( TrkA and p75NTR ) activator. BNN27 activates ERK1/2/AKT. BNN27 enhances NGF-induced differentiation/axonal growth and inhibits JNK after NGF withdrawal. BNN27 reduces Amyloid-β plaques, gliosis, and pro-inflammatory cytokines, and rescues synaptic/cholinergic deficits, neurogenesis, and working memory. BNN27 can be used in research on Alzheimer's disease, amyotrophic lateral sclerosis, diabetic retinopathy, inflammatory hyperalgesia, anxiety disorders, and multiple sclerosis [1] [2] [3] [4] [5] [6] [7] [8] [9].
In Vivo, BNN27 (10 mg/kg/day; subcutaneous injection; sustained release; 60 days) reduces hippocampal Aβ plaque burden, attenuates astrogliosis and microgliosis, rescues synaptic degeneration of CA2 mossy fibers, restores basal forebrain cholinergic soma size, reduces p75NTR+/ChAT+ neurons, promotes adult hippocampal neurogenesis, partially rescues dysregulated hippocampal proteins, and improves hippocampus-dependent spatial working memory in 5xFAD mice without altering TrkA+/ChAT+ neurons or entorhinal cortex neurofilament/myelin[1]. BNN27 (3 mg/day; intraperitoneal injection; daily; from gestational day 3 to E13.5) reduces apoptotic Caspase-3-positive sensory neurons in embryonic dorsal root ganglia of NGF-deficient mice[3]. BNN27 (10 mg/kg; intraperitoneal injection; once every two days; 4 weeks) reverses diabetes-induced loss of bNOS/TH amacrine cell markers and reduces cleaved caspase-3, but does not reduce TUNEL+ retinal cell death in STZ diabetic rats[6]. BNN27 (19-470 mM; topical ophthalmic eye drops; daily; 7 days) restores diabetes-induced loss of NFL, bNOS, and TH immunoreactivity in the retina of diabetic Sprague-Dawley rats in a dose-dependent manner, with 94 and 470 mM being effective and 19 mM ineffective, and these effects are mediated by TrkAR[4]. BNN27 (90 mg/kg; intraperitoneal injection; single injection; 30 minutes before the open field test) suppresses locomotor and exploratory behavior in both sexes, whereas BNN27 (10-30 mg/kg; intraperitoneal injection; single injection; 30 minutes before each behavioral test) produces male-specific alterations in exploratory behavior in the open field, light-dark box, or hole board test, without anxiolytic-like effects[5]. BNN27 (3-6 mg/kg; intraperitoneal injection; single injection 40 minutes before testing) increases the time spent in the light compartment of the light-dark box, indicating an anxiolytic-like effect in the light-dark box test[8]. BNN27 (10-30 mg/kg; intraperitoneal injection; single injection; 30 minutes before sampling) produces dose- and sex-dependent changes in neurotransmitters and hormones, in which low doses increase hippocampal GABA, glutamine, and glutamate turnover as well as prefrontal glutamate in males, whereas 30 mg/kg alters testosterone and progesterone levels[5]. BNN27 (2-50 mg/kg; intraperitoneal injection; daily; 7 days) reverses diabetes-induced retinal neuronal/glial injury and inflammation in STZ diabetic rats through a TrkA-dependent mechanism, without reducing TUNEL+ retinal cell death[6]. BNN27 (100 mg/kg; intraperitoneal injection; once daily; for 4 consecutive days) reverses CFA-induced inflammatory hyperalgesia in mice[7]. BNN27 (10-100 mg/kg; intraperitoneal injection; once daily; for 4 consecutive days) produces transient analgesia at 3 hours in CFA-induced inflammatory hyperalgesia in mice and reduces paw TNF-α without affecting edema[7]. BNN27 (10-100 mg/kg; intraperitoneal injection; single dose 30 minutes before CFA) produces transient analgesia at 3 hours and reduces corticosterone in CFA-induced inflammatory hyperalgesia in mice[7]. BNN27 (2.86 mg/day; subcutaneous implantation; 21-day release; implanted on day 8 and day 29) protects mature oligodendrocytes and myelin during Cuprizone-induced demyelination while reducing microgliosis and astrogliosis[9]. BNN27 (2.86 mg/day; subcutaneous implantation; 21-day release; during 3-week remyelination after 6 weeks of Cuprizone treatment) does not improve remyelination after Cuprizone withdrawal, but reduces OPC number and glial cell activation[9].
In Vitro, BNN27 (100 nM) protects against Aβ42-induced cytotoxicity in P7 hippocampal NSCs through Trk and p75NTR receptors, but does not restore Aβ42-reduced BrdU (+)/Nestin (+) proliferation[1]. BNN27 (10 μM; 2 h) is not a P-gp substrate in MDCK-MDR1 cells, with an efflux ratio of 3.7[2]. BNN27 (18 h) shows high passive BBB permeability in the BBB-PAMPA assay, with a Pe of 12.7 μcm/s[2]. BNN27 (10 μM; 2 h) is not a BCRP substrate in Caco-2 monolayer cells, with an efflux ratio of 1.5[2]. BNN27 (1 pM-1 μM) effectively displaces [3H]-DHEA bound to membranes of HEK293TrkA transfected cells (Ki = 1.8 nM)[3]. Immobilized BNN27 (4°C overnight) directly pulls down recombinant TrkA[3] in vitro. BNN27 (100 nM; 15 min) activates TrkA by inducing phosphorylation of Y490, Y674/675, and Y785 in CHOTrkA cells, but does not activate TrkB or TrkC[3]. BNN27 (100 nM; 60 min) promotes TrkA localization to lipid raft microdomains in HEK293TrkA cells[3]. BNN27 (100 nM; 24 h) inhibits serum deprivation-induced apoptosis in PC12 cells in a TrkA-dependent manner[3].
References:
[1]. Kokkali M, et al. Multimodal beneficial effects of BNN27, a nerve growth factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer’s disease. Molecular Psychiatry. 2025 Jun;30(6):2265-83.
[2]. Bennett JP, et al. Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis. Biochemical pharmacology. 2016 Oct 01;117:68-77.
[3]. Pediaditakis I, et al. Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation. Neuropharmacology. 2016 Dec;111:266-282.
[4]. Ibán-Arias R, et al. Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019 Nov;257(11):2429-2436.
[5]. Kokras N, et al. Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats. Psychopharmacology. 2020 Aug;237(8):2435-2449.
[6]. Ibán-Arias R, et al. The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes. Diabetes. 2018 Feb;67(2):321-333.
[7]. Poulaki S, et al. Analgesic and Anti-Inflammatory Effects of the Synthetic Neurosteroid Analogue BNN27 during CFA-Induced Hyperalgesia. Biomedicines. 2021 Sep 09;9(9):1185.
[8]. Fragkiadaki E, et al. Effects of low doses of the novel dehydroepiandrosterone (DHEA) derivative BNN27 in rat models of anxiety. Psychopharmacology. 2024 Feb;241(2):341-350.
[9]. Bonetto G, et al. The novel synthetic microneurotrophin BNN27 protects mature oligodendrocytes against cuprizone-induced death, through the NGF receptor TrkA. Glia. 2017 Aug;65(8):1376-1394.
In Vivo, BNN27 (10 mg/kg/day; subcutaneous injection; sustained release; 60 days) reduces hippocampal Aβ plaque burden, attenuates astrogliosis and microgliosis, rescues synaptic degeneration of CA2 mossy fibers, restores basal forebrain cholinergic soma size, reduces p75NTR+/ChAT+ neurons, promotes adult hippocampal neurogenesis, partially rescues dysregulated hippocampal proteins, and improves hippocampus-dependent spatial working memory in 5xFAD mice without altering TrkA+/ChAT+ neurons or entorhinal cortex neurofilament/myelin[1]. BNN27 (3 mg/day; intraperitoneal injection; daily; from gestational day 3 to E13.5) reduces apoptotic Caspase-3-positive sensory neurons in embryonic dorsal root ganglia of NGF-deficient mice[3]. BNN27 (10 mg/kg; intraperitoneal injection; once every two days; 4 weeks) reverses diabetes-induced loss of bNOS/TH amacrine cell markers and reduces cleaved caspase-3, but does not reduce TUNEL+ retinal cell death in STZ diabetic rats[6]. BNN27 (19-470 mM; topical ophthalmic eye drops; daily; 7 days) restores diabetes-induced loss of NFL, bNOS, and TH immunoreactivity in the retina of diabetic Sprague-Dawley rats in a dose-dependent manner, with 94 and 470 mM being effective and 19 mM ineffective, and these effects are mediated by TrkAR[4]. BNN27 (90 mg/kg; intraperitoneal injection; single injection; 30 minutes before the open field test) suppresses locomotor and exploratory behavior in both sexes, whereas BNN27 (10-30 mg/kg; intraperitoneal injection; single injection; 30 minutes before each behavioral test) produces male-specific alterations in exploratory behavior in the open field, light-dark box, or hole board test, without anxiolytic-like effects[5]. BNN27 (3-6 mg/kg; intraperitoneal injection; single injection 40 minutes before testing) increases the time spent in the light compartment of the light-dark box, indicating an anxiolytic-like effect in the light-dark box test[8]. BNN27 (10-30 mg/kg; intraperitoneal injection; single injection; 30 minutes before sampling) produces dose- and sex-dependent changes in neurotransmitters and hormones, in which low doses increase hippocampal GABA, glutamine, and glutamate turnover as well as prefrontal glutamate in males, whereas 30 mg/kg alters testosterone and progesterone levels[5]. BNN27 (2-50 mg/kg; intraperitoneal injection; daily; 7 days) reverses diabetes-induced retinal neuronal/glial injury and inflammation in STZ diabetic rats through a TrkA-dependent mechanism, without reducing TUNEL+ retinal cell death[6]. BNN27 (100 mg/kg; intraperitoneal injection; once daily; for 4 consecutive days) reverses CFA-induced inflammatory hyperalgesia in mice[7]. BNN27 (10-100 mg/kg; intraperitoneal injection; once daily; for 4 consecutive days) produces transient analgesia at 3 hours in CFA-induced inflammatory hyperalgesia in mice and reduces paw TNF-α without affecting edema[7]. BNN27 (10-100 mg/kg; intraperitoneal injection; single dose 30 minutes before CFA) produces transient analgesia at 3 hours and reduces corticosterone in CFA-induced inflammatory hyperalgesia in mice[7]. BNN27 (2.86 mg/day; subcutaneous implantation; 21-day release; implanted on day 8 and day 29) protects mature oligodendrocytes and myelin during Cuprizone-induced demyelination while reducing microgliosis and astrogliosis[9]. BNN27 (2.86 mg/day; subcutaneous implantation; 21-day release; during 3-week remyelination after 6 weeks of Cuprizone treatment) does not improve remyelination after Cuprizone withdrawal, but reduces OPC number and glial cell activation[9].
In Vitro, BNN27 (100 nM) protects against Aβ42-induced cytotoxicity in P7 hippocampal NSCs through Trk and p75NTR receptors, but does not restore Aβ42-reduced BrdU (+)/Nestin (+) proliferation[1]. BNN27 (10 μM; 2 h) is not a P-gp substrate in MDCK-MDR1 cells, with an efflux ratio of 3.7[2]. BNN27 (18 h) shows high passive BBB permeability in the BBB-PAMPA assay, with a Pe of 12.7 μcm/s[2]. BNN27 (10 μM; 2 h) is not a BCRP substrate in Caco-2 monolayer cells, with an efflux ratio of 1.5[2]. BNN27 (1 pM-1 μM) effectively displaces [3H]-DHEA bound to membranes of HEK293TrkA transfected cells (Ki = 1.8 nM)[3]. Immobilized BNN27 (4°C overnight) directly pulls down recombinant TrkA[3] in vitro. BNN27 (100 nM; 15 min) activates TrkA by inducing phosphorylation of Y490, Y674/675, and Y785 in CHOTrkA cells, but does not activate TrkB or TrkC[3]. BNN27 (100 nM; 60 min) promotes TrkA localization to lipid raft microdomains in HEK293TrkA cells[3]. BNN27 (100 nM; 24 h) inhibits serum deprivation-induced apoptosis in PC12 cells in a TrkA-dependent manner[3].
References:
[1]. Kokkali M, et al. Multimodal beneficial effects of BNN27, a nerve growth factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer’s disease. Molecular Psychiatry. 2025 Jun;30(6):2265-83.
[2]. Bennett JP, et al. Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis. Biochemical pharmacology. 2016 Oct 01;117:68-77.
[3]. Pediaditakis I, et al. Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation. Neuropharmacology. 2016 Dec;111:266-282.
[4]. Ibán-Arias R, et al. Effect of topical administration of the microneurotrophin BNN27 in the diabetic rat retina. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019 Nov;257(11):2429-2436.
[5]. Kokras N, et al. Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats. Psychopharmacology. 2020 Aug;237(8):2435-2449.
[6]. Ibán-Arias R, et al. The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes. Diabetes. 2018 Feb;67(2):321-333.
[7]. Poulaki S, et al. Analgesic and Anti-Inflammatory Effects of the Synthetic Neurosteroid Analogue BNN27 during CFA-Induced Hyperalgesia. Biomedicines. 2021 Sep 09;9(9):1185.
[8]. Fragkiadaki E, et al. Effects of low doses of the novel dehydroepiandrosterone (DHEA) derivative BNN27 in rat models of anxiety. Psychopharmacology. 2024 Feb;241(2):341-350.
[9]. Bonetto G, et al. The novel synthetic microneurotrophin BNN27 protects mature oligodendrocytes against cuprizone-induced death, through the NGF receptor TrkA. Glia. 2017 Aug;65(8):1376-1394.