Contributions
Abstract: 124
Type: Oral
The promotion of use-dependent synaptic plasticity has been proposed as a key mechanism at the basis of the clinical effects of rehabilitation in patients with multiple sclerosis (MS). Long-term potentiation (LTP) is the most studied form of synaptic plasticity, and has the potential to minimize the clinical expression of neuronal damage because it can restore the excitability of neurons that have lost part of their synaptic inputs.
As long as surviving neurons can undergo LTP to compensate ongoing neuronal death, the clinical manifestation of brain damage can be compensated.
Exercise promotes LTP. Running exercise in mice, in fact, results in increased LTP compared to non-exercising animals, and importantly, this form of experience-dependent synaptic plasticity can be enhanced by specific pharmacological treatments.
For example, the stimulation of glutamate NMDA receptors is an essential requirement for the induction of LTP. LTP induction also requires the stimulation of cannabinoid CB1 receptors, and exercise is an effective tool to enhance endocannabinoid levels in humans, also suggesting that the LTP-promoting effects of rehabilitation are mediated at least in part by the up-regulation of endogenous cannabinoid system. Thus, pharmacological stimulation of cannabinoid CB1 receptors could be a useful complement of rehabilitation to enhance synaptic plasticity and favor recovery.
Dopamine is a third receptor system involved in LTP induction and maintenance. LTP is in fact abolished by pharmacological blockade of dopamine D1 receptors or by genetic ablation of these receptors, and it is not surprising therefore that extensive literature exists pointing that stimulation of dopamine receptors with levodopa or other dopamine agonists enhances spontaneous and exercise-driven motor recovery.
A forth player in LTP induction and maintenance is BDNF. LTP is in fact disrupted in mice lacking BDNF, and human subjects carrying a genetic variant of BDNF, the non-val/val genotype exhibit poor or absent LTP in response to stimulation of the motor cortex or to exercise therapy. In this respect, SSRI are very effective in enhancing BDNF levels and the plasticity promoting effects of this neurotrophin. Fluoxetine treatment is for example able to increase BDNF concentration, and to promote in parallel LTP maintenance. Accordingly, fluoxetine-induced plasticity can be useful to promote recovery of function following rehabilitation treatment.
Disclosure: Dr. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi, Teva. His preclinical and clinical research was supported by grants from Bayer, Biogen, Merck Serono, Novartis e Teva.
Abstract: 124
Type: Oral
The promotion of use-dependent synaptic plasticity has been proposed as a key mechanism at the basis of the clinical effects of rehabilitation in patients with multiple sclerosis (MS). Long-term potentiation (LTP) is the most studied form of synaptic plasticity, and has the potential to minimize the clinical expression of neuronal damage because it can restore the excitability of neurons that have lost part of their synaptic inputs.
As long as surviving neurons can undergo LTP to compensate ongoing neuronal death, the clinical manifestation of brain damage can be compensated.
Exercise promotes LTP. Running exercise in mice, in fact, results in increased LTP compared to non-exercising animals, and importantly, this form of experience-dependent synaptic plasticity can be enhanced by specific pharmacological treatments.
For example, the stimulation of glutamate NMDA receptors is an essential requirement for the induction of LTP. LTP induction also requires the stimulation of cannabinoid CB1 receptors, and exercise is an effective tool to enhance endocannabinoid levels in humans, also suggesting that the LTP-promoting effects of rehabilitation are mediated at least in part by the up-regulation of endogenous cannabinoid system. Thus, pharmacological stimulation of cannabinoid CB1 receptors could be a useful complement of rehabilitation to enhance synaptic plasticity and favor recovery.
Dopamine is a third receptor system involved in LTP induction and maintenance. LTP is in fact abolished by pharmacological blockade of dopamine D1 receptors or by genetic ablation of these receptors, and it is not surprising therefore that extensive literature exists pointing that stimulation of dopamine receptors with levodopa or other dopamine agonists enhances spontaneous and exercise-driven motor recovery.
A forth player in LTP induction and maintenance is BDNF. LTP is in fact disrupted in mice lacking BDNF, and human subjects carrying a genetic variant of BDNF, the non-val/val genotype exhibit poor or absent LTP in response to stimulation of the motor cortex or to exercise therapy. In this respect, SSRI are very effective in enhancing BDNF levels and the plasticity promoting effects of this neurotrophin. Fluoxetine treatment is for example able to increase BDNF concentration, and to promote in parallel LTP maintenance. Accordingly, fluoxetine-induced plasticity can be useful to promote recovery of function following rehabilitation treatment.
Disclosure: Dr. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, Genzyme, GW Pharmaceuticals, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi, Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi, Teva. His preclinical and clinical research was supported by grants from Bayer, Biogen, Merck Serono, Novartis e Teva.