Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

Abstract

1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Po0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist K i 's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Po0.001).3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABA A (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis .

Piracetam improves mitochondrial dysfunction following oxidative stress

“…Piracetam is known to enhance cerebral glucose metabolism ( Heiss et al ., 1988 ). Moreover, Piracetam antagonizes inhibition of human erythrocyte D ‐glucose transport by barbiturates, diazepam, melatonin, and galanin ( Naftalin et al ., 2004 ). Thus, enhanced glucose transport in the cells might contribute to the stabilization of mitochondrial function during serum deprivation.…”

“…Piracetam's improving effects on the fluidity of aged synaptosomal membranes could easily explain the beneficial effects of piracetam on age‐related deficits of several mechanisms of signal transduction (receptor density and function, transmitter release) ( Stoll et al ., 1992 ; Muller et al ., 1999 ), since these mechanisms are disturbed in the aging brain probably due to a decrease of membrane fluidity. Piracetam's recently reported effects on impaired glucose uptake might also be a consequence of its effects on membrane fluidity ( Naftalin et al ., 2004 ). On the other hand, evidences that piracetam's beneficial effects on the fluidity of aged mitochondrial membranes might contribute to its therapeutic efficacy are rather indirect and orginate from observations that piracetam might improve glucose uptake and utilization as well as ATP production ( Domanska‐Janik & Zaleska, 1977 ; Benzi et al ., 1985 ; Heiss et al ., 1988 ).…”

Thyrotropin-Releasing Hormone Analogs

“…However, utilization of benzodiazepines as TRH-R modulators would be accompanied by CNS depression, thereby limiting their usefulness as reagents to study TRH receptor biology. It is of interest to note that more recently, TRH has also been found to antagonize the inhibition of glucose transport by barbiturates, diazepam, melatonin and galanin in human erythrocytes [70].…”

Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects

“…A drug which has been extensively characterized in this respect is the metabolic enhancer piracetam [115], which shows no antioxidant properties but exhibits pronounced mitochondrial protection ex vivo as well as in vitro [116][117][118] Evidences that piracetam might improve disturbed mitochondrial function originate from observations that piracetam improves glucose uptake and utilization as well as ATP production [119][120][121][122]. In line with these data are our previous observations of significant mitochondrial protection and enhanced ATP synthesis by piracetam against experimentally induced oxidative as well as nitrosative stress in vitro and after ex vivo treatment, where again aged animals with well-characterized mitochondrial dysfunction benefited most [116].…”