Table 2.

Non-exhaustive list of in vivo uses of TTFC for neurological applications between 2005 and 2022.

Medicinal Product	Biological Interest	Administration and Dose	Experimental Model	Observed Effects	Ref.
TTFC used alone
TTFC	neuronal protection (ALS)	Intramuscular 1 μg	male and female SOD1-G93A mice	Modulated the levels of NLRP3 and caspase-1 in spinal cord, EDL and SOL muscles Reduced IL-6 levels in tissues drastically affected by ALS Potential therapeutic molecule	[37]
TTFC	neuropsychiatric disorders (depression)	intramuscular 20–60 μg/kg	adult male Wistar-Kyoto rats	Levels of hippocampal and frontal cortical BDNF increased Levels of TNF-alpha in the same areas decreased Potential utility of TTFC in PD-depression comorbidity	[38]
TTFC	neuronal protection (spinal MN degeneration)	direct spinal infusion (total amount of ~42 ng/rat) intramuscular (total amount of ~400 ng/rat)	adult male Wistar rats	Attenuated the AMPA-induced astrogliosis Increased the phosphorylation of the TrkA receptor at Y490 in spinal MNs Intramuscular > spinal infusion	[39]
TTFC	neuronal protection (PD)	intraperitoneal 0.5 mg/kg	male 8-week-old Sprague–Dawley rats	TTFC as pre-treatment Prevented decrease in DA, TH, DAT, VMAT-2 Uses in neuronal dysfunctions	[40]
TTFC	neuronal protection (AD, effect on learning and memory)	medial septum (local administration) 100 ng	adult male Wistar rats	Protection of the cholinergic system After administration of a toxic peptide, TTFC functionally maintained memory Lower level of cell degeneration Maintained cell morphology	[41]
TTFC	neuronal protection (post-methamphetamine treatment)	intramuscular 40 μg/kg	adult male C57BL/6J mice	Only three injections of TTFC Prevented the striatal tyrosine hydroxylase (TH) and DA transporter (DAT) decrease induced by METH Potential for TTFC use against the damage induced by METH	[42]
TTFC	neuronal protection (restorative effect)	intramuscular 20 µg/kg	adult male Wistar rats	Neurodegeneration caused by 6-OHDA Prevented the progression of asymmetrical motor behavior Decreased the neurodegenerative process (fewer dark cells) Decreased of striatal neurodegeneration after 28 days	[43]
Naked DNA encoding for TTFC	neuronal protection (cerebral ischemia)	intramuscular 200 µg	adult male Mongolian gerbils	Improved neurological status and survival Elimination of ischemia-induced motor hyperactivity and oxidative stress Reduced nitrite levels, O2-production and lipid peroxidation Improved SOD activity	[36]
Naked DNA encoding for TTFC	neuronal protection (ALS disease)	intramuscular 300 µg	SOD1-G93A mice	Delayed onset of symptoms Extended the mouse survival	[29]
TTFC used as a fusion protein
TTFC fused with rAAV8, CMV and eGFP	tracing study (connectivity map)	hippocampal injection 1 µL	adult male and female tdTomatoJ mice	Exploration of the sequence of cerebellar-hippocampal connections Displayed eGFP positive cells in the rhinal cortex and subiculum	[44]
TTFC fused with GDNF	neuronal protection (ALS disease)	intramuscular 300 µg	SODG93A mice	Improved mice survival Delayed onset symptoms Improved motor function Activation of survival signals in SC Treatment by fusion protein was less efficient as GDNF alone	[45]
TTFC fused with GFP	study of neuronal network (study of nerve injury)	/	transgenic mice (NPY-Cre, ZWX)	Allowed to study the consequence of an injury and especially the CNS reorganization circuits	[46]
TTFC fused with IGF-1	neuronal protection(age related nerve alteration)	intramuscular 10 µg	old control FVB and DBA mice	Prevented age-related alterations to nerve terminal at the NMJs Prevented Ca2+ dependent contraction No effect with TTFC alone	[47]
TTFC fused with GFP or β-galactosidase	study of neuronal network (muscle specific spinal motor circuitry)	intramuscular 10.57–19.2 µg/mL	new born BalbC/J mice	Fusion protein kept TTFC retrograde transport properties intact With low injected doses, fusion protein spread on other muscles	[48]
TTFC fused with SOD1	neuronal delivery (protein)	intra- cerebroventricular	adult male C57BL6 mice	Enhanced protein distribution and persistence throughout the CNS Injection mode difficult to manage	[24]
Other forms of TTFC (analog, complex, conjugate)
125I-TTFC	retrograde transport (spinal cord)	intramuscular 10 µg of radiolabeled TTC	transgenic mice (C57BL6, SOD193A)	Quantification of the net retrograde axonal transport Monitoring of a new therapy	[49]
PEISH-based NP with HC	neuronal delivery (gene therapy)	subcutaneous 150 μL of dispersion (conc. 7.5 µg pegylated HC per 2 µg of pDNA)	male 4-month old Wistar rats	PEISH-HC-functionalized NP In day 5, GFP expressed in dorsal root ganglia neurons Gene therapy strategies	[50]
Synthetic analog of TTFC, Tet1-peptide	neuronal delivery (small molecules)	intramuscular 1 µL/g of body weight)	young adult male heterozygous rats	Delivery of small molecules into the CNS without toxicity	[28]
TTFC chemically coupled to GDNF	neuronal delivery (therapeutics)	intramuscular 60–100 µg	adult male mice	The conjugate maintained both TTFC transport and GDNF neuroprotection properties Improved GDNF delivery into MN GDNF persistence in spinal cord section	[51]