RESUMEN
Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100â¯nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670-nm light (4â¯J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10â¯days, followed by injection of the parkinsonian neurotoxin MPTP (50â¯mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10â¯days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.
Asunto(s)
Encéfalo/metabolismo , Encéfalo/efectos de la radiación , Terapia por Luz de Baja Intensidad/métodos , Trastornos Parkinsonianos/radioterapia , Transcriptoma/efectos de la radiación , Animales , Núcleo Caudado/metabolismo , Núcleo Caudado/efectos de la radiación , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de la radiación , Masculino , Ratones Endogámicos BALB C , Trastornos Parkinsonianos/metabolismo , Porción Compacta de la Sustancia Negra/metabolismo , Porción Compacta de la Sustancia Negra/efectos de la radiación , Putamen/metabolismo , Putamen/efectos de la radiaciónRESUMEN
We have used the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model to explore whether (i) the neuroprotective effect of near infrared light (NIr) treatment in the SNc is dose-dependent and (ii) the relationship between tyrosine hydroxylase (TH)+ terminal density and glial cells in the caudate-putamen complex (CPu). Mice received MPTP injections (50 mg/kg) and 2 J/cm2 NIr dose with either 2 d or 7 d survival period. In another series, with a longer 14 d survival period, mice had a stronger MPTP regime (100 mg/kg) and either 2 J/cm2 or 4 J/cm2 NIr dose. Brains were processed for routine immunohistochemistry and cell counts were made using stereology. Our findings were that in the 2 d series, no change in SNc TH+ cell number was evident after any treatment. In the 7 d series however, MPTP insult resulted in â¼45% reduction in TH+ cell number; after NIr (2 J/cm2) treatment, many cells were protected from the toxic insult. In the 14 d series, MPTP induced a similar reduction in TH+ cell number. NIr mitigated the loss of TH+ cells, but only at the higher dose of 4 J/cm2; the lower dose of 2 J/cm2 had no neuroprotective effect in this series. The higher dose of NIr, unlike the lower dose, also mitigated the MPTP- induced increase in CPu astrocytes after 14 d; these changes were independent of TH+ terminal density, of which, did not vary across the different experimental groups. In summary, we showed that neuroprotection by NIr irradiation in MPTP-treated mice was dose-dependent; with increasing MPTP toxicity, higher doses of NIr were required to protect cells and reduce astrogliosis.
Asunto(s)
Neuronas Dopaminérgicas/efectos de la radiación , Gliosis/radioterapia , Rayos Infrarrojos/uso terapéutico , Intoxicación por MPTP/radioterapia , Trastornos Parkinsonianos/radioterapia , Porción Compacta de la Sustancia Negra/efectos de la radiación , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Animales , Astrocitos/patología , Astrocitos/efectos de la radiación , Núcleo Caudado/patología , Núcleo Caudado/efectos de la radiación , Recuento de Células , Supervivencia Celular/efectos de la radiación , Neuronas Dopaminérgicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Gliosis/patología , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/análisis , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/patología , Putamen/patología , Putamen/efectos de la radiación , Tirosina 3-Monooxigenasa/análisisRESUMEN
We explored whether 810nm near-infrared light (NIr) offered neuroprotection and/or improvement in locomotor activity in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. Mice received MPTP and 810nm NIr treatments, or not, and were tested for locomotive activity in an open-field test. Thereafter, brains were aldehyde-fixed and processed for tyrosine hydroxylase immunohistochemistry. Our results showed that MPTP-treated mice that were irradiated with 810nm NIr had both greater locomotor activity (â¼40%) and number of dopaminergic cells (â¼20%) than those that were not. In summary, 810nm (as with 670nm) NIr offered neuroprotection and improved locomotor activity in MPTP-treated mice.
Asunto(s)
Neuronas Dopaminérgicas/efectos de la radiación , Rayos Infrarrojos , Actividad Motora/efectos de la radiación , Trastornos Parkinsonianos/radioterapia , Porción Compacta de la Sustancia Negra/efectos de la radiación , Animales , Recuento de Células , Neuronas Dopaminérgicas/metabolismo , Terapia por Luz de Baja Intensidad , Masculino , Ratones , Ratones Endogámicos BALB C , Trastornos Parkinsonianos/metabolismo , Porción Compacta de la Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/análisisRESUMEN
Low dose whole-body gamma-irradiation is recently reported to confer neuroprotection against optic nerve crush and contusive spinal cord injury. Here, we extended the study and investigated whether the pretreatment of a single low dose whole-body gamma-irradiation may have a preventive effect in MPTP-induced model of PD. One week after the last MPTP treatment, HPLC determination of striatal dopamine and immunostaining for tyrosine hydroxylase (TH), CD11b and GFAP to detect dopamine neurons and associated glial reaction in the substantia nigra pars compacta (SNpc) were performed. MPTP treatment reduced striatal DA levels significantly; nigral TH immunoreactivity was reduced to a lower extent; robust gliosis was also observed in SNpc. We found that 3.5 Gy irradiation but not 5.5 Gy restores the level of DA and its metabolites decreased by MPTP. However, there was no difference in the number of TH positive neurons between 3.5 Gy irradiated and saline treated mice after MPTP treatment. Irradiation also did not have obvious influence on microgliosis and astroglial reaction induced by MPTP treatment. In conclusion, the results presented here demonstrated that low dose whole-body gamma-irradiation renders neuroprotection against MPTP-mediated damage of striatal dopaminergic nerve fibers, though it does not seem to influence the MPTP-induced reduction of SNpc dopaminergic neurons and associated glial responses.