Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor.
One of the main causes of
neurodegeneration involves changes in the expression of
neurotrophins (NTs) and/or their receptors (
TrkA,
TrkB,
TrkC and
p75NTR). Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor
pharmacokinetic properties, such as reduced
bioavailability and low metabolic stability, the
hyperalgesia, the inability to penetrate the
blood–brain barrier and the short
half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.[1]
For this reason, several efforts have been made to develop neurotrophin mimetics (small molecules and
peptidomimetics) that can modulate the action of the neurotrophin receptors (
Trks and p75NTR) and possess drug-like pharmacokinetic and
pharmacodynamic profiles. Specifically, these mimetics can be classified as TrkA and TrkB receptor agonists and p75NTR modulators/antagonists.[2]
Synthetic small molecule neurotrophin mimetics
TrkA agonists
Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing
apoptosis in primary
hippocampal neurons.[3] The non-peptidic TrkA agonist MT2 protects neurons from
Aβ amyloid-mediated death in
NGF-deficient neurons[4] and talaumidin and its derivatives show
neuroprotective effects, promoting
neurite outgrowth in
PC12 cells.[5] Furthermore, the
peptidomimeticcerebrolysin is known for its
protective role in
Alzheimer's disease (AD).[6] It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a
double-blind trial.[7] In addition, the cyclic peptide
tavilermide (MIM-D3), acting as a partial
TrkA receptor agonist, showed a relevant improvement of
cognitive capacities of treated aged rats, leading to a selective survival of the
cholinergic neurons.[8]
A
phase 3 clinical trial of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of
carvacrol by inducing neurite outgrowth and
phosphorylation of TrkA in cells deprived of NGF.[9] The same research group investigated the neurotrophic effect of the well-known antibiotic
doxycycline and they found that it prevents amyloid toxicity in a Drosophila model of AD both in vitro and in vivo and induces neuritogenesis by activation of TrkA.[10]
Additionally, some novel
DHEA derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative,
BNN-27,[11] induces phosphorylation of TrkA in neuronal and
glial cells in culture and it exerts
antiapoptotic effect without inducing
hyperalgesia.[12] Moreover, it improved memorizing abilities in rats after i.p. administration[13] and restored the
myelin loss in cuprizone-induced
demyelinationin vivo.[14] Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists.[15][16] In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its
downstream signaling pathways, and promote
cell survival of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in
dorsal root ganglia and anti-amyloid activity in hippocampal neurons.[15][16]
TrkB agonists
TrkB agonists have received extensive interest from the scientific community resulting in the synthesis and biological evaluation of a large number of mimetics.
Deoxygedunin, with a selective TrkB activity, is able to promote
axon regeneration in topical treatments.[17] Furthermore, it shows efficacy in two
Parkinson's disease (PD) animal models, leading to the protection of
locomotor function and the reduction of
neuronal death in
dopaminergic neurons.[18] A number of studies corroborated that the
flavonoid 7,8-Dihydroxyflavone (7,8-DHF) shows neuroprotection in PD and
Huntington's disease (HD) models[19][20] together with
antioxidant activity[21] and enhancement of motor neuronal survival, motor function and spine density in
amyotrophic lateral sclerosis (ALS) model.[22] The benzothiazole
riluzole exerts neuroprotective effects by increasing
BDNF and
GDNF levels with improvement of motor neuron survival. It has been approved for the treatment of ALS and delays the onset of
ventilator-dependence or
tracheostomy in some people and may increase survival by two to three months.[23] Furthermore, several combinations of riluzole with other drugs are in clinical trials (NCT02588677, NCT03127267).
Brimonidine exerts neuroprotective effects in
retinal ganglion cells (RGCs) through up-regulation of the expression of BDNF in these cells.[24] It is used in the treatment of
glaucoma as eye drops to reduce
intraocular pressure (IOP) under the brand name Lumify®. Different drugs, used against PD also behave as neurotrophin mimetics such as
rotigotine,
selegiline,
rasagiline,
memantine and
levodopa interacting with TrkB and increasing BDNF expression.[25] Furthermore, of particular note, the groups of F. Longo and S. Massa discovered small molecule neurotrophic mimetics exhibiting
specificity for TrkB at
nanomolar concentrations.[26] In particular,
LM22A-4, prevents neuronal death in in vitro models of AD, HD and PD.[27]
Among the peptidomimetic TrkB agonists, the dimeric dipeptide GSB-106 showed neurotrophic and neuroprotective effects by specific activation of TrkB and its
signaling pathways.[28][29] Furthermore, the tricyclic dimeric peptide TDP6 acts as a TrkB agonist mimicking BDNF and induces
autophosphorylation of TrkB in primary
oligodendrocyte cultures, leading to oligodendrocyte myelination.[30] Regarding DHEA derivatives, the C17-spiroepoxy analogue,
BNN-20, binds with high affinity to TrkB, showing antiapoptotic activity in vitro. Its neuroprotective activity was analyzed in the
Weaver mouse genetic model of PD in which long term administration of BNN-20 protects the dopaminergic neurons by mimicking BDNF and induces antiapoptotic, antioxidant and anti-inflammatory effects.[11][31]
p75NTR modulators
In this class it is worthwhile to highlight the small non-peptide molecules LM22A-24 and
LM11A-31 developed by Longo and Massa. Through the modulation of
p75NTR activity, these compounds downregulate degenerative and upregulate trophic signaling.[32] In particular, LM11A-31 was found to inhibit several pathophysiological mechanisms involved in AD and related to p75NTR.[33][34] Oral administration in AD mice models reduces degeneration of cholinergic neurites.[34] Furthermore, by a direct activation of p75NTR signaling and inhibition of apoptotic pathway, it improves motor function in a
spinal cord injury (SCI) mice model and leads to an antiapoptotic effect in mice after
traumatic brain injury (TBI).[35][36] In February 2017, a
phase 2 clinical trial started focusing on the evaluation of the safety of LM11A-31 in mild to moderate AD (NCT03069014). This study was completed in June 2020, but the results have not been published yet.
Another drug belonging to the class of p75NTR antagonists is THX-B, which inhibits NGF-p75NTR binding and prevents the death of RGCs in
axotomy and glaucoma. In addition, in combination with LM22A-24, THX-B delays the loss of retinal structure, prevents RGC degeneration and preserves
ganglion cell layer-
inner plexiform layer thickness with a better efficacy compared to LM22A-24.[37] Finally, a p75NTR antagonist, EVT901, was able to improve functional outcomes in two models of traumatic brain injury.[38] Furthermore it was found to reduce inflammation in vivo in the TGFAD344 rat model of AD.[39]
The first discovered non-protein neurotrophic natural product was
lactacystin, isolated from a culture broth of Streptomyces sp.[40]Magnolol and
honokiol, the main constituents of Magnolia officinalis and Magnolia obovata stem bark, have been reported to have neurotrophic activity in primary cultured rat cortical by enhancing the BDNF expression.[41][42]Merrilactone A, jiadifenin,
jiadifenolide, (1R,10S)-2-oxo-3,4-dehydroxyneomajucin, jiadifenoxolane A, (2R)-hydroxynorneomajucin, 11-O-debenzoyltashironin,tricycloillicinone, and bicycloillicinone, natural products of the Illicium family have been shown to promote neurite outgrowth in primary cultures of cortical neurons of fetal rats.[40][41] Neurotrophic properties are also possessed by several members of the Lycopodiumalkaloids (
huperzine A, lyconadins, complanadine A and B, and nankakurine A and B). Studies have shown that huperazine A can elevate the levels of NGF and BDNF. Synthesis of NGF can be upregulated by administration of cyathanediterpenoids specifically
erinacines,
scabronines and cyrneines.[40]
Beside natural products, there are some small molecules of natural origin that exert neurotrophic activities such as:
Panaxytriol (promotes NGF-induced neurite outgrowth in PC-12 cells); 7,8-
dihydroxyflavone (TrkB activator);
Deoxygedunin (BDNF mimetic); Kansuinin E (promotes neurotrophic activity, most likely through TrkA activation);
Tripchlorolide (stimulates expression of BDNF mRNA);
Fucoxanthin (increases BDNF production and activates PKA/CREB pathway);
Silibinin (Activate hippocampal ROS-BDNF-TrkB patway).[40][42]
References
^Josephy-Hernandez, Sylvia; Jmaeff, Sean; Pirvulescu, Iulia; Aboulkassim, Tahar; Saragovi, H. Uri (January 2017). "Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm". Neurobiology of Disease. 97 (Pt B): 139–155.
doi:
10.1016/j.nbd.2016.08.004.
ISSN0969-9961.
PMID27546056.
S2CID8469340.
^Gudasheva, Tatiana A.; Povarnina, Polina Y.; Tarasiuk, Aleksey V.; Seredenin, Sergey B. (September 2021). "Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: Design and pharmacological properties". Medicinal Research Reviews. 41 (5): 2746–2774.
doi:
10.1002/med.21721.
ISSN0198-6325.
PMID32808322.
S2CID221163909.
^Alvarez, X. A.; Cacabelos, R.; Laredo, M.; Couceiro, V.; Sampedro, C.; Varela, M.; Corzo, L.; Fernandez-Novoa, L.; Vargas, M.; Aleixandre, M.; Linares, C. (January 2006). "A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer's disease". European Journal of Neurology. 13 (1): 43–54.
doi:
10.1111/j.1468-1331.2006.01222.x.
ISSN1351-5101.
PMID16420392.
^Alvarez, X. A.; Cacabelos, R.; Sampedro, C.; Aleixandre, M.; Linares, C.; Granizo, E.; Doppler, E.; Moessler, H. (2010-12-15). "Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer's disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin". European Journal of Neurology. 18 (1): 59–68.
doi:
10.1111/j.1468-1331.2010.03092.x.
ISSN1351-5101.
PMID20500802.
S2CID8434356.
^Sisti, Flávia Malvestio; dos Santos, Neife Aparecida Guinaim; do Amaral, Lilian; dos Santos, Antonio Cardozo (2021-03-05). "The Neurotrophic-Like Effect of Carvacrol: Perspective for Axonal and Synaptic Regeneration". Neurotoxicity Research. 39 (3): 886–896.
doi:
10.1007/s12640-021-00341-1.
ISSN1029-8428.
PMID33666886.
S2CID232121683.
^Longo, Frank M.; Massa, Stephen M. (July 2013). "Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease". Nature Reviews Drug Discovery. 12 (7): 507–525.
doi:
10.1038/nrd4024.
ISSN1474-1776.
PMID23977697.
S2CID33597483.
^Gudasheva, T. A.; Logvinov, I. O.; Antipova, T. A.; Seredenin, S. B. (July 2013). "Brain-derived neurotrophic factor loop 4 dipeptide mimetic GSB-106 activates TrkB, Erk, and Akt and promotes neuronal survival in vitro". Doklady Biochemistry and Biophysics. 451 (1): 212–214.
doi:
10.1134/s1607672913040121.
ISSN1607-6729.
PMID23975404.
S2CID3231624.