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Table1 A summary of NTFs delivery vectors in CNS and their possible improvement pathways

From: Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: focus on available approaches

Vectors/Routes

Neurotrophic factors

Disease model

Related pathways

Possible consequence of neurotrophic factor

Cell/stem cell

Mesenchymal stem cells

IGF-1

SCI rats

Axonal Extension/survival

Extended the axons and improved the corticospinal motor neurons

BDNF

MS mice

Inflammation

Raised BDNF and GAD67and the

L-4,-10,-1, diminished TNF-α and IFN-γ and improved re-myelination

GDNF

PD rats

Dopamine pathway

Enhanced sprouting of dopaminergic terminals

NT-3

SCI rats

Axonal extension/survival

Induced motor function, axonal regrowth and survival

NGF

BDNF

NT-3

TBI rats

Apoptosis

Enhanced p-Akt and decreased caspase-3

BDNF

PD rats

 

Enhanced TH positive cell number, PCNA expression and motor function

CNTF

SCI rats

 

Improved BBB test performance

BDNF

HD mice

Neurogenesis

Diminished striatum atrophy and anxiety and raised neurogenesis and life span

Neural stem cells

BDNF

AD mice

Synaptic pathways

Improved synaptic density and behavioral function

GDNF

ALS rats

 

Caused differentiation in astrocytes

Neurotrophic factor secreting cells

BDNF GDNF

NGF

HD rats

 

Could migrate to lesion site

PD rats

Survival pathways

Enhanced survival of DA neurons and improved motor and behavioral functions

PD rats

Regeneration

Upregulated dopamine level and regenerated the network of DA nerve end in striatum

MS mice

 

Decreased the disease symptom and enhanced life span

HD

rats

Neuroprotection

Improved behavioral function

SCI rats

Remyelination/survival

Improved myelin and raised the number of oligodendrocyte

MS rats

 

Enhanced MBP and Olig2 proteins expression

Immune cells

GDNF

PD rats

Axonal regeneration/survival

Improved open field activity, regenerated axons and preserved TH positive neurons

NTN

PD rats

Synaptic pathway/survival

Preserved TH positive neurons, improved synapses and behavioral function

GDNF

PD mice

 

Could cross the BBB and delivered GDNF to the DA neurons

GDNF

PD mice

Inflammation/proliferation

Enhanced motor function and DA neuron number and reduced α-synuclein and inflammation

GDNF

PD mice

Dopamine pathway

Raised TH positive neurons number and motor/non motor function

C2C12 cells

CNTF

AD mice

Synaptic pathway/survival

Restored synapses and survival signaling and cognitive function

hUCBCs

VEGF

GDNF

ALS mice

 

Improved behavioral performance and increased the mean life-span

HEK293

GDNF

PD mice

 

Enhanced TH positive neurons and motor function

Virus

Adeno-associated virus

IGF-I

ALS rats

 

Improved motor function in male rats

BDNF

SCI rats

Apoptosis

decreased caspase-3 and upregulated NG2 expressing cell number

EPO

PD rats

 

Bettered DA neurons population and motor function

GDNF

Healthy rats

 

Rapamycin regulated GDNF releasing

IGF-1

SMA mice

Apoptosis

Restrained apoptosis

BDNF

SCI rats

Axonal regeneration

Regenerated axons but worsened motor function and caused spasticital symptoms

BDNF

AD mice

Synaptic pathway/survival

Improved behavioral function, neuronal survival and synapses

Lentivirus

BDNF

SCI rats

Axonal expansion

Elongated axons in neurons

BDNF

NT-3

SCI rats

Axonal regeneration

Regenerated and remyelinated axons

NT-3

SCI

rat

 

Improved neurons, locomotor function and diminished

the astrocyte level

NT-3

NT-3/SHH

SCI mice

Axonal regeneration

Raised axonal regeneration, remyelination and enhanced the number of glial cells

GDNF

AD mice

 

Enhanced learning and memory and BDNF level but decreased cognition

Biomaterial

Microspheres

GDNF

PD rats

 

Ameliorated rotational behavior and extended TH positive fibers

Chitosan

NGF

Healthy rats

 

Upgraded bioavailability of NGF up to 14 fold

PNIPAAm-g-PEG

PNIPAAm-g-MC

BDNF

SCI rats

Axonal regeneration

Enhanced axonal regeneration

HAMC hydrogel

EPO

Stroke mice

Neurogenesis, inflammation, apoptosis

Enhanced neurogenesis, mediated inflammation and diminished the apoptosis

 

BDNF

SCI rat

Survival pathway/inflammation

Progressed neuronal survival and decreased the expression of pro-inflammatory cytokines

DCH

NGF

Healthy mice

Cholinergic system

Caused hypertrophy of cholinergic neurons

Gelatin nanoparticles

bFGF

PD rats

Dopamine pathway

Improvement of DA function in synapses

Collagen hydrogel

MSCs

GDNF

Healthy rats

Survival pathway

Moderated neuroglia activation, improved cell survival and GDNF secretion

collagen conduits

NT-3

Healthy rats

Axonal extension

Improved axonal extension

Hyaluronan hydrogel

NT-3

SCI rats

Axonal regeneration

Regenerated and enlarged the axons, did not induce the astroglial response and improve motor function

BDNF

Stroke mice

Axonal regeneration/survival

Regenerated axons and caused migration and survival of immature neurons

Fibrin

NT-3

SCI rats

Synaptic pathway

Advanced neuronal fiber density and diminished glial scar

NT3

PDGF

with ESNPCs

SCI rat

Survival pathway

Enhanced ESNPC derived mature neurons and survival of ESNPC in the lesion site

RDP

BDNF

Healthy mice

Survival

Reduced infarct volume and neural loss

nano-particle polyion complex with PEG/PGA copolymers

BDNF

Stroke mice

 

upgraded memory and cognitive function and sustained myelin base proteins

PLGA/ nanoparticles/ poloxamer 188 (PX) coated

BDNF

TBI mice

 

Restored cognition and neurological loss

HyStem®-C hydrogel

BDNF

Stroke rats

 

Improved sensorimotor function tests, diminished infarct volume and glial markers

PLGA/GO electrospun nanofibers

IGF-1 BDNF

SCI rats

 

Increased the lesion site population of neurons, locomotor function and moderated the formation of cavity

Ultrasound& MBs

 

BDNF

Healthy mice

 

Enhanced BDNF concentration in target site

GDNF

Healthy rats

 

Could cross through BBB and were delivered locally in an non-invasive way

BDNF

GDNF

NTN

Healthy mice

 

Started molecular signaling of hippocampal pyramidal neurons inside the nucleus

NTN

Healthy mice

 

Upregulated the NTN levels in caudoputamen and substantia nigra, began the signaling pathway

GDNF

PD rats

 

Improved motor and behavioral functions

Pump

 

BDNF

HD mice

 

Mediated function and motor coordination, lingered life time and downregulated the microglial reaction

CNTF

MS rats

Inflammation

Restricted inflammation, diminished demyelination, axonal deficit and neuronal death

NGF

HD mice

Cholinergic system, neurogenesis

Upregulated ChAT and VAChT levels, elevated neurogenesis

BDNF

SCA1 mice

Synaptic pathway

Reduced motor loss and synaptic deficit of Purkinje neurons

Intranasal

 

BDNF, NT-4, CNTF and EPO

Healthy rats

survival pathway

Upregulated the NTF concentrations and initiated cell survival pathway

NGF

stroke rats

survival pathway, maturation

Improved neural cell survival and maturation

bFGF spray

AD rats

Cholinergic system

Enhanced ChAT and acetylcholinesterase activity and decreased hippocampal neuronal degeneration

NGF

TBI rats

Amyloid pathway

Reduced Aβ1-42 deposits and recovered the motor and behavioral function

GDNF

PD rats

 

Increased TH positive neurons and DA cells and several constant dose of NTF were more efficient

  1. NTF neurotrophic factor, GDNF Glial cell-derived neurotrophic factor, NGF Nerve growth factor, bFGF; Basic fibroblast growth factor, BDNF Brain derived neurotrophic factor, NT-4 Neurotrophin-4, CNTF Ciliary neurotrophic factor, EPO Erythropoietin, NTN Neurturin, IGF-1 Insulin-like growth factor-1, NT-3 Neurotrophin-3, PDGF Platelet-derived growth factor, RDP Rabies virus glycoprotein, DCH Diblock polypeptide hydrogels, SHH Sonic hedgehog, MSCs Mesenchymal stem cells, ESNPCs Embryonic stem cell-derived neural progenitor cell, SCI Spinal cord injury, MS Multiple sclerosis, PD Parkinson’s disease, TBI Traumatic brain injury, HD Huntington’s disease, AD Alzheimer’s disease, ALS Amyotrophic lateral sclerosis, SMA Spinal muscular atrophy, SCA1 Spinocerebellar ataxia type 1, GAD67 Glutamic acid decarboxylase 67, TNF-α Tumor necrosis factor alpha, IFN-γ Interferon gamma, pAkt protein kinase B, TH Tyrosine hydroxylase, PCNA Proliferating cell nuclear antigen, DA Dopaminergic, MBP Myelin basic protein, BBB test Basso-Beattie-Bresnahan test, BBB Blood- brain barrier, NG2 Precursor of oligodendrocyte lineage, ChAT Choline acetyltransferase, VAChT Acetylcholine transporter, Aβ Amyloid beta, PLGA/GO Poly lactic-co-glycolic acid/Graphene oxide PEG/PGA Poly (glutamic acid)-poly (ethylene glycol), C2C12 cells Myoblast line, hUCBCs Human umbilical cord blood cells, HEK293 Human embryonic kidney 293 cell line