Biomedical subjects

Daniel L Alkon

Publications and source records attributed to Daniel L Alkon.

40 records · Page 3Linked to original sources

PubMed2002

Isolation of protein subpopulations undergoing protein-protein interactions.

A new method is described for isolating and identifying proteins participating in protein-protein interactions in a complex mixture. The method uses a cyanogen bromide-activated Sepharose matrix to isolate proteins that are non-covalently bound to other proteins. Because the proteins are accessible to chemical manipulation, mass spectrometric identification of the proteins can yield information on specific classes of interacting proteins, such as calcium-dependent or substrate-dependent protein interactions. This permits selection of a subpopulation of proteins from a complex mixture on the basis of specified interaction criteria. The new method has the advantage of screening the entire proteome simultaneously, unlike the two-hybrid system or phage display, which can only detect proteins binding to a single bait protein at a time. The method was tested by selecting rat brain extract for proteins exhibiting calcium-dependent protein interactions. Of 12 proteins identified by mass spectrometry, eight were either known calcium-binding proteins or proteins with known calcium-dependent protein interactions, indicating that the method is capable of enriching a subpopulation of proteins from a complex mixture on the basis of a specific class of protein interactions. Because only naturally occurring interactions of proteins in their native state are observed, this method will have wide applicability to studies of protein interactions in tissue samples and autopsy specimens, for screening for perturbations of protein-protein interactions by signaling molecules, pharmacological agents or toxins, and screening for differences between cancerous and untransformed cells.

Animals↗

PubMed2002

Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.

Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.

Animals↗

PubMed2002

Impairment of hippocampal CA1 heterosynaptic transformation and spatial memory by beta-amyloid(25-35).

In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before beta-amyloid (Abeta) plaque formation. It has not been established whether the link between soluble Abeta and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that Abeta(25-35), an active form of Abeta, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 microg/site). The Abeta microinjections did not affect single-pulse-evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular theta; was dramatically reduced by the Abeta(25-35) injection. Spatial memory of the water maze task was also impaired by the bilateral icv Abeta(25-35) injections, while bilateral microinjections of the same dose of Abeta(35-25) was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular theta;, or producing memory impairments. Thus restoring the synaptic plasticity involved in this associative activation of cholinergic and GABAergic inputs may offer an important therapeutic target in the treatment of early Abeta-induced memory decline.

Amyloid beta-Peptides↗

PubMed2002

Depressed or demented: common CNS drug targets?!

A body of evidence emerging in antidepressant and antidementia research has revealed a convergence of molecular events known to regulate neuronal plasticity in learning and memory with molecular actions of drugs for the treatment of depression. Many antidepressants are reported to have positive impact on learning and memory. These include agents acting through monoaminergic neurotransmitter systems, non-monoaminergic transmitter systems, and hormones. On the other hand, agents that appear to have memory-enhancing or antidementia value are frequently found to exhibit antidepressant activity in patients and animal depression models. It is becoming clear that the comorbidity of depression and dementia does not occur by chance, but rather is an inevitable consequence of pathologic relationships between the conditions. Molecular mechanisms and cascades that underlie memory may be shared by mood regulation and are vulnerable to stress and injuries. This review focuses on recent findings regarding effects of a variety of agents on dementia and depression and their common molecular mechanisms as well as their differences. A better understanding of the key underlying molecular components whose changed activities have dramatic influences on mood and cognition may lead to the development of novel and more effective therapeutic agents for the treatment of depression and dementia. In this review, some of the recent findings that suggest novel therapeutic strategies are also highlighted.

Animals↗