FGL

FGL (Fibroblast Growth Loop) is a synthetic 15-amino acid peptide derived from the second fibronectin type III module of Neural Cell Adhesion Molecule (NCAM) that functions as an NCAM mimetic by binding to and activating fibroblast growth factor receptor 1 (FGFR1). This peptide has demonstrated extensive neuroprotective, neurotrophic, and anti-inflammatory effects in preclinical studies, including mobilization of neural stem cells, enhancement of synaptic plasticity, and protection against ischemic and amyloid-beta-induced neuronal damage. FGL has advanced to early-stage human clinical trials for neurodegenerative diseases, showing favorable safety and tolerability profiles in Phase I studies with intranasal administration.

Cognitive Enhancement and Memory

FGL facilitates long-term potentiation (LTP) in the dentate gyrus without affecting basal synaptic transmission, enhancing both the induction and maintenance of synaptic plasticity in vivo ^[1][8]. The peptide induces long-lasting improvements in memory consolidation across multiple learning paradigms, including fear conditioning and spatial learning tasks, by strengthening synaptic transmission and promoting synaptogenesis in hippocampal neurons ^[15]. In models of cognitive impairment, FGL ameliorated working memory deficits induced by neonatal phencyclidine treatment, bringing performance nearly to control levels ^[4].

Neuroprotection and Neural Regeneration

FGL provides robust neuroprotection against ischemic injury, protecting hippocampal neurons from oxygen-glucose deprivation both in vitro and in vivo models of transient global ischemia, maintaining metabolic and presynaptic neuronal activity ^[12]. The peptide significantly reduces neuropathological signs of Alzheimer's disease, including amyloid deposits, tau phosphorylation, microglial activation, and neuronal death induced by amyloid-beta peptides ^[11][6]. FGL mobilizes endogenous neural stem cells from both the subventricular zone and hippocampus, increasing proliferative activity and promoting remyelination after stroke, suggesting potential for regenerative therapy ^[2][3].

Synaptic and Structural Plasticity

Treatment with FGL induces substantial alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats, increasing the ratio of mushroom to thin spines and enhancing the frequency of multivesicular bodies and coated pits ^[2]. The peptide preserves presynaptic protein (synaptophysin) expression and prevents age-related loss of astrocyte-synaptic contacts, modifying glial-synaptic relationships to maintain hippocampal function ^[14]. FGL preferentially promotes oligodendroglial phenotype development, making it a promising agent for facilitating remyelination in demyelinating neurological disorders ^[3].

Anti-Inflammatory Effects

FGL functions as a novel anti-inflammatory agent in the aged hippocampus, attenuating increased expression of markers of activated microglia (CD11b+ and MHCII+) and reducing pro-inflammatory cytokine interleukin-1beta production ^[7][9]. The peptide reverses age-related decline in insulin-like growth factor-1 (IGF-1) while reducing interferon-gamma levels, promoting neuronal IGF-1 release and enhancing CD200 ligand expression through ERK-dependent mechanisms ^[13]. By stimulating neuronal CD200 expression and enhancing IL-4 release from glial cells, FGL suppresses microglial activation and age-related neuroinflammation ^[7].

Clinical Safety Profile

FGL (as FGLL) has completed Phase I clinical trials in healthy human volunteers with favorable safety outcomes. In a study of 24 healthy male volunteers (mean age 42 years, range 24-55), single intranasal doses of 25, 100, and 200mg were well tolerated with no clinically notable abnormalities in ECG recordings, vital signs, or laboratory tests ^[5]. Only three subjects (13%) reported five adverse events, which were generally mild and transient, including a brief burning sensation in the nose (<3 minutes) in two subjects at the 200mg dose and runny eyes (<2 minutes) in one subject at 25mg ^[5].

Preclinical Toxicity Studies

Extensive preclinical safety evaluations in rats, dogs, and monkeys demonstrated systemic exposure in both plasma and cerebrospinal fluid after parenteral or intranasal administration with no systemic toxicity observed ^[5]. The no observed adverse effect level (NOAEL) was established at the high dose of 1000 mg/kg in animal studies ^[5]. Genetic toxicology studies were uniformly negative: the Ames mutagenicity test showed no evidence of mutagenicity, FGL did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, and no micronuclei formation was detected in rat bone marrow ^[5].

Potential Concerns

One study reported that FGL treatment alone in non-pathological young adult rats caused a 40% reduction in CA1 pyramidal cells, suggesting the peptide may be potentially disruptive under non-pathological conditions while remaining protective in disease states ^[6]. Additionally, in a mouse kindling model of epilepsy, both tested doses (2 and 10 mg/kg) accelerated seizure onset rather than preventing it, raising concerns about potentially promoting hyperexcitable neural networks in certain contexts ^[10]. These findings suggest FGL may have context-dependent effects that warrant careful consideration for therapeutic applications.

Pharmacokinetics

Following intranasal administration in humans, measurable plasma concentrations appeared after 100mg and 200mg doses, demonstrating dose-dependent systemic exposure with no accumulation concerns from single-dose administration ^[5]. The peptide crosses the blood-brain barrier and achieves cerebrospinal fluid exposure sufficient for central nervous system effects ^[5].