Pre-conditioning with Remote Photobiomodulation Modulates the Brain Transcriptome and Protects Against MPTP Insult in Mice.

Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100 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 (4 J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50 mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 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.

The effect of different doses of near infrared light on dopaminergic cell survival and gliosis in MPTP-treated mice.

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 ∼45% 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.

Amino acid concentrations in hypothalamic and caudate nuclei during microwave-induced thermal stress: analysis by microdialysis.

Exposure to radiofrequency radiation (RFR) may produce thermal responses. Extracellular amino acid concentrations in the hypothalamus (Hyp) and caudate nucleus (CN) were measured by using in vivo microdialysis before and during exposure to RFR. Under urethane anesthetic, each rat was implanted stereotaxically with a nonmetallic microdialysis probe and temperature probe guides and then placed in the exposure chamber. The rat laid on its right side with its head and neck placed directly under the wave guide. Temperature probes were placed in the left brain, right brain, face (subcutaneously), left tympanum, and rectum. Each microdialysis sample was collected over a 20 min period. The microdialysis probe was perfused for 2 h before the rat was exposed to 5.02 GHz radiation (10 microseconds pulse width, 1000 pulses/s). The right and left sides of the brain were maintained at approximately 41.2 and 41.7 degrees C, respectively, throughout a 40 min exposure period. Initially when the brain was being heated to these temperatures, the time-averaged specific absorption rates (SARs) for the right and left sides of the brain were 29 and 40 W/kg, respectively. Concentrations of aspartic acid, glutamic acid, serine, glutamine, and glycine in dialysate were determined by using high-pressure liquid chromatography with electrochemical detection. In the Hyp and CN, the concentrations of aspartic acid, serine, and glycine increased significantly during RFR exposure (P < .05). These results indicate that RFR-induced thermal stress produces a general change in the amino acid concentrations that is not restricted to thermoregulatory centers. Changes in the concentrations of glutamic acid (Hyp, P = .16; CN, P = .34) and glutamine (Hyp, P = .13; CN, P = .10) were not statistically significant. Altered amino acid concentrations may reveal which brain regions are susceptible to damage in response to RFR-induced thermal stress.

[Total bioelectric activity of various structures of the brain in low-intensity microwave irradiation]. / Summarnaia bioélektricheskaia aktivnost' razlichnykh struktur golovnogo mozga v usloviiakh nizkointensivenykh MKV-obluchenii.

In experiments with thirty rabbits the influence of thirty-minute microwave irradiation (1.5 GHz, pulse intensity 0.3 mW/cm2; pulsed modes: 0.12 Hz, 16 ms or 1000 Hz, 0.4 ms; pack-pulsed mode: pulse frequency 1000 Hz, pack frequency 0.12 Hz) on the total bioelectrical activity of brain structures was studied. The reliable effect was detected only in hippocamp. The total bioelectrical activity of cortex, caudate nucleus, hypothalamus, amygdala and septum was not changed reliably in animal group studied. The reaction of hippocamp was displayed as amplification of theta-range in spectrum within of normal functioning.

In vivo biological effects of stereotactic radiosurgery: a primate model.

Single-fraction, closed skull, small-volume irradiation (radiosurgery) of intact intracranial structures requires accurate knowledge of radiation tolerance. We have developed a baboon model to assess the in vivo destructive radiobiological effects of stereotactic radiosurgery. Three baboons received a single-fraction, 150-Gy lesion of the caudate nucleus, the thalamus, or the pons using the 8-mm diameter collimator of the gamma unit. Serial standard neurodiagnostic tests (neurological examination, computed tomographic scan, magnetic resonance imaging, stable xenon-enhanced computed tomographic scan of cerebral blood flow, somatosensory and brain stem evoked potentials, and myelin basic protein levels of cerebrospinal fluid) were compared with preoperative studies. Magnetic resonance imaging revealed the development of a lesion at the target site between 45 and 60 days after irradiation. Deterioration of the brain stem evoked potentials preceded imaging changes when the lesion encroached on auditory pathways. Myelin basic protein levels increased subsequent to imaging changes. Postmortem neuropathological examination confirmed a well-demarcated radionecrosis of the target volume. The baboon model appears to be an excellent method to study the in vivo biological effects of radiosurgery.