Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function

Abstract

The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.

The Changes of Mitochondria in Substantia Nigra and Anterior Cerebral Cortex of Hepatic Encephalopathy Induced by Thioacetamide

“…Mitochondria were fission and fusion constantly. The rapid modulation of mitochondrial dynamics occurs in response to physiological stimulation, including apoptotic stimulation (Spinazzi et al, 2008;Morciano et al, 2016), oxidative stress (Partyka et al, 2016;Rogov et al, 2018) to maintain the metabolic balance (Stockburger et al, 2016;Agnihotri et al, 2017). Therefore, mitochondrial functions were inseparable from the mitochondria morphology.…”

The use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?

“…Hence, L-theamine may serve as prophylaxis and treatment for AD 57 . Further, Piracetam exerts its neuroprotective effects on PC12 cells, SH-SY5Y cells, and SH-SY5Y APPwt cells by improving synaptic plasticity, maintaining mitochondrial dynamic and neuritogenesis 58 . In addition, Noopept protects PC12 cells against Aβ25-35 induced toxicity by inhibiting of oxidative damage, preventing of calcium overload, suppressing apoptosis, attenuating hyperphosphorylation of tau, and ameliorating the neural outgrowth induced by Aβ25-35 59 .…”

Prevention of Alzheimer's disease by treating mild cognitive impairment with combinations chosen from eight available drugs

“…A review indicated favorable effects on neurotransmission, neuroplasticity, and microcirculation [60]. Another report showed that the increased neurite length after piracetam treatment was accompanied by increased expression of the synaptic marker, GAP43, thus improving neural plasticity [61]. After oxidative stress induced by sodium nitroprusside and serum deprivation, piracetam induced a nearly complete recovery of mitochondrial membrane potential and ATP levels; and piracetam protected individual complexes of the mitochondrial respiratory chain after treatment with different respiratory chain complex inhibitors [62].…”