gms | German Medical Science

Objective: High frequency stimulation (HFS) of deep brain structures has evolved as a powerful therapeutic alternative for the treatment of movement disorders. Despite its clinical success, the exact mechanisms of action have remained unknown. In addition to the immediate functional efficacy of HFS, studies in animal models have recently suggested a long-term neuroprotective effect based on restoration in striatal dopamine levels and nigral dopamine neurons. Here, the impact of DBS on the expression of neurotrophic factors (NF) was analyzed in the rat.

Methods: 6-OHDA lesioned rats (male Wistar, age 21 days, weighing ~300g) received HFS or sham stimulation in the STN using an implantable microstimulation system. Group size was 4-5 animals each. STN-HFS was initiated 5 days after the intrastriatal 6-OHDA lesion and continuous (current intensity 50 or 100 µA, frequency 131 Hz, pulse width 52 µs). After 14 days of stimulation animals were sacrificed by decapitation and brains were shock frozen in nitrogene-cooled methylbutane. Striata and frontal cortices were dissected with the aid of Paxinos and Watson’s rat brain atlas, using a cryostate. Levels of glial-derived NF (GDNF), brain-derived NF (BDNF) and vascular endothelial growth factor (VEGF) were analyzed in homogenates of striatal and cortical tissue, both by quantitative PCR and colorimetric ELISA.

Results: Successful stimulation was assessed clinically by involuntary movements. PCR and ELISA concordantly revealed an upregulatory effect of HFS on all three neurotrophic factors investigated, both in striatal and cortical tissues. The effect was more pronounced on mRNA levels than on protein levels. Relative quantification (RQ) values of mRNA in stimulated animals as compared to placebo were: BDNF cortex: 2.0; BDNF striatum: 36.2; GDNF cortex: 1.3, GDNF striatum: 1.6; VEGF cortex: 1.2; VEGF striatum: 1.6. Protein levels, as assessed by ELISA (in pg, always sham ± SD versus stimulation ± SD, with respective p-values) were: BDNF cortex: 179 ± 12 vs 202 ± 30 (p = 0.5053), BDNF striatum 179 ± 25 vs. 238 ± 55 (p = 0.0855), GDNF cortex 67 ± 8 vs. 76 ± 25 (p = 0.532), GDNF striatum 71 ± 10 vs. 78 ± 8 (p = 0.1978), VEGF cortex 31 ± 3 vs 56 ± 17 (p = 0.0289), VEGF striatum 25 ± 8 vs. 42 ± 14 (p = 0.0305). Bilateral effects were observed despite unilateral stimulation.

Conclusions: Our results suggest that the upregulation of NF after DBS may participate in the long-term therapeutic efficacy and potentially neuroprotective effects of this therapy.