Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.
- MeSH
- buňky zadních rohů míšních MeSH
- mícha MeSH
- myši MeSH
- neuralgie * etiologie terapie MeSH
- nociceptory * MeSH
- prasata MeSH
- technika přenosu genů MeSH
- zadní rohy míšní MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.
- MeSH
- amyotrofická laterální skleróza genetika patofyziologie terapie MeSH
- atrofie MeSH
- degenerace nervu genetika patofyziologie terapie MeSH
- Dependovirus metabolismus MeSH
- interneurony patologie MeSH
- lidé MeSH
- malá interferující RNA aplikace a dávkování MeSH
- messenger RNA genetika metabolismus MeSH
- mícha diagnostické zobrazování patologie patofyziologie MeSH
- motorické evokované potenciály MeSH
- motorické neurony patologie MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- pia mater patologie patofyziologie MeSH
- prasata MeSH
- primáti MeSH
- progrese nemoci MeSH
- regulace genové exprese MeSH
- sbalování proteinů MeSH
- superoxiddismutasa 1 genetika metabolismus MeSH
- technika přenosu genů * MeSH
- umlčování genů * MeSH
- vývoj svalů MeSH
- zánět patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Sledovaním pôsobenia anti-inflamačných liekov po poškodení miechy sa zistilo, že lieky ako methylprednisolon (MP), minocyklín (MC) a takrolimus (FK506) majú limitovaný účinok na výsledný post-traumatický status. V súvislosti s možnou neuroprotekciou poškodenej miechy sa v súčasnosti študujú účinky statínov, ako ďalšej skupiny liekov u ktorej bol zistený anti-inflamačný efekt. Neuroprotekcia traumatického poškodenia CNS bola zatiaľ takmer výlučne orientovaná na monoterapie, ktoré ale zlyhali v klinických skúškach. V súčasnosti sa predpokladá, že pre úspešnú terapiu po poškodení CNS je vhodnejšia kombinácia liečiv s doplňujúcimi sa účinkami, ako zameranie sa na jeden cieľ s mnohými účinnými látkami.
Investigation of anti-inflammatory drugs action following traumatic spinal cord injury revealed that methylprednisolon (MP), mi- nocycline (MC) and tacrolimus (FK506) have limited effects on the fi- nal post-traumatic outcome. Statins, the group of clinically used drugs that were found to have anti-inflammatory effects following CNS are re- cently examined to improve neuroprotection within injured spinal cord. Neuroprotection of CNS following traumatic injury is almost exclusi- vely focused on monotherapies, all of which have failed in multicenter clinical trials. Recently, it is assumed that combination of agents with complementary targets and effects rather than focusing on a single tar- get with multiple agents facilitates the development of successful com- bination therapy in CNS injury.
- Publikační typ
- abstrakt z konference MeSH
Poranenie miechy je komplexná porucha sprevádzaná kom- plikovanými patofyziologickými pochodmi, ktoré sa podieľajú na rozvoji sekundárneho poškodenia miechy. Aj keď možnosti farmakoterapie sú pri liečbe poranenia miechy obmedzené, potlaèenie neuroinflamácie protizápalovými lieèivami je jednou z možnosti ovplyvnenia poškodenia miechového tkaniva. Minocyklín (MC) je modifikovaný tetracyklín, ktorý má okrem anti-bakteriálneho aj anti-inflamaèný úèinok. V našom experi- mente sme sledovali neuroprotektívny vplyv liečby minocyklínom, ktorý sme podávali po tlakovom poškodeni miechy potkana. V experimente sme hodnotili vplyv MC na histologicky a neurologicky post-traumaticky status. Neuroprotektívne úèinky MC sa prejavili len èiastoène, v rostrálnej èasti poškodeného segmentu miechy sme zistili štatistický významný nárast zachovanej bielej a sivej miechovej hmoty v porovnaní s kontrolnou sku- pinou. Neurologický status však nebol MC lieèbou zlepšený, èo znamená, že pri tlakovom poškodení miechy má MC limitovaný neuroprotektívny potenciál.
Traumatic spinal cord injury (SCI) is a disorder with multifaceted post-traumatic pathophysiology that generates secondary spinal cord injury. Pharmacological therapy of SCI is limited, however inhibitions of neuroinflammation by anti-inflammatory drugs can ame- liorate secondary SCI. MC is a second generation tetracycline that has both, anti-bacterial and anti-inflammatory effects. We investigated the neuroprotective effect of MC treatment on histological and neurological outcome following compression injury of rat spinal cord. We observed MC neuroprotective effects in the rostral part of the injured spinal cord in which significant increased in preserved spinal cord white and matter was found in comparison with placebo group. However, the final neu- rological outcome of animals was not improved by MC treatment, what means, that MC has limited neuroprotectiove effects following spinal cord compression.
- Klíčová slova
- kompresia, inflamácia, miecha, potkan,
- MeSH
- minocyklin MeSH
- Publikační typ
- abstrakty MeSH
